ES2662026T3 - New renin inhibitor - Google Patents

Abstract

A compound of formula [I]; ** Formula ** wherein R 1 is a cycloalkyl or an alkyl, R 22 is 1) an optionally substituted aryl, 2) an optionally substituted pyridyl, 3) an optionally substituted pyrazolopyridyl, 4) an indole optionally substituted, 5) an optionally substituted benzofuranyl, 6) an optionally substituted quinolyl, 7) an optionally substituted chromanyl, 8) an optionally substituted dihydrobenzofuranyl, 9) an optionally substituted indazolyl, 10) an optionally substituted pyrrolopyridinyl, 11) an optionally substituted benzisoxazolyl substituted, 12) an optionally substituted indolinyl, 13) an optionally substituted quinazolinyl, 14) an optionally substituted dihydroquinazolinyl, 15) an optionally substituted furopyridyl, 16) an optionally substituted isoquinolyl, 17) an optionally substituted pyrrolopyrimidinyl, 18) an optionally substituted tetrahydroquinolyl , 19) an optionally substituted tetrahydroindazolyl, 20) a tetrah optionally substituted idrocyclopentapyrazolyl, 21) an optionally substituted pyrrolyl, 22) an optionally substituted imidazolyl, 23) an optionally substituted pyrazolyl, 24) an optionally substituted thienyl, 25) an optionally substituted thiazolyl, 26) an optionally substituted triazolyl, 27) a pyrimidinyl optionally substituted, 28) an optionally substituted pyrazyl, 29) an optionally substituted imidazopyridinyl, or 30) an optionally substituted pyrrolopyrazyl, R is a C1-C4 alkyl group, one of R4 and R5 is a group selected from 1) an optionally substituted carbamoyl with an alkyl that is optionally substituted with 1 or 2 phenyls, 2) an alkyl optionally substituted with an alkoxy optionally substituted with a halogen or a phenyl; a halogen; a hydroxyl; an amino optionally substituted with 1 or 2 alkyls; or cyano; and 3) an alkoxycarbonyl, or a pharmaceutically acceptable salt thereof, the other, R3 and R6, are the same or different, a hydrogen atom, an optionally substituted carbamoyl, an optionally substituted alkyl or alkoxycarbonyl, or a pharmaceutically acceptable salt thereof. .

Description

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DESCRIPTION

New renin inhibitor Technical field

The present invention relates to new compounds that are useful as a medicament, especially as a renin inhibitor, or pharmaceutically acceptable salts thereof and for use, a process for its preparation or intermediates thereof.

Prior art

Renin inhibitors are expected as a medicine for the prevention and / or treatment of diseases such as hypertension, heart failure, diabetic nephropathy and 3,4-substituted piperidine derivatives, for example (Patent Related Bibliography 1). But the morpholine derivative is not described in the literature.

Also in WO 2008/153182 some morpholine derivatives are described but they are compounds having a formula I of the present invention wherein R is a hydrogen atom (Bibliography related to Patents 2).

Reference List

Patent related bibliography

Patent related bibliography 1: document WO06 / 069788WO (US 2009 / 0312304A)

Bibliography related to Patents 2: WO2008 / 153182WO (US 2010 / 0240644A)

Bibliography related to Patents 3: document WO2012 / 124775 (EP 2 687 518)

WO 2012/124775 describes renin inhibitors, but only specific structures with unsubstituted R4 and R5 substituents in the morpholino radical are described.

Description of the invention

Technical problem

The present invention provides new compounds that have excellent activity to inhibit renin. Solution to the problem

To solve the problem, the authors of the present invention have studied extensively to find new compounds that have excellent activity to inhibit renin and finally completed the present invention.

The present invention is as follows;

(1) A compound of the formula [I];

image 1

wherein R1 is a cycloalkyl or an alkyl,

R22 is 1) an optionally substituted aryl, 2) an optionally substituted pyridyl, 3) an optionally substituted pyrazolopyridyl, 4) an optionally substituted indole, 5) an optionally substituted benzofuranyl, 6) an optionally substituted quinolyl, 7) an optionally substituted chromanyl , 8) an optionally substituted dihydrobenzofuranyl, 9) an optionally substituted indazolyl, 10) a

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optionally substituted pyrrolopyridinyl, 11) an optionally substituted benzisoxazolyl, 12) an optionally substituted indolinyl, 13) an optionally substituted quinazolinyl, 14) an optionally substituted dihydroquinazolinyl, 15) an optionally substituted furopyridyl, 16) an optionally substituted isoquinolyl, 17) a pyrrolopim optionally substituted, 18) an optionally substituted tetrahydroquinolyl, 19) an optionally substituted tetrahydroindazolyl, 20) an optionally substituted tetrahydrocyclopentapyrazolyl, 21) an optionally substituted pyrrolyl, 22) an optionally substituted imidazolyl, 23) an optionally substituted pyrazolyl, 24) an optionally substituted thienyl substituted, 25) an optionally substituted thiazolyl, 26) an optionally substituted triazolyl, 27) an optionally substituted pyrimidinyl, 28) an optionally substituted pyrazyl, 29) an optionally substituted imidazopyridinyl, or 30) an optionally substituted pyrrolopyrazyl do,

R is a C1-C4 alkyl group,

one of R1 2 3 4 and R5 is a group selected from

1) a carbamoyl optionally substituted with an alkyl that is optionally substituted with 1 or 2 phenyl,

2) an alkyl optionally substituted with an alkoxy optionally substituted with a halogen or a phenyl; a halogen; a hydroxyl; an amino optionally substituted with 1 or 2 alkyls; or cyano; Y

3) an alkoxycarbonyl,

or a pharmaceutically acceptable salt thereof,

the other, R3 and R6 7 8, are the same or different, a hydrogen atom, an optionally substituted carbamoyl, an optionally substituted alkyl or alkoxycarbonyl, or a pharmaceutically acceptable salt thereof.

(2) The compound according to section (1), wherein R3 and R6 are both hydrogen atoms, or a pharmaceutically acceptable salt thereof.

(3) The compound according to any one of items (1) to (2), wherein the substituents of 1) the optionally substituted aryl, 2) the optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 4) the optionally substituted indole, 5) optionally substituted benzofuranyl, 6) optionally substituted quinolyl, 7) optionally substituted chromanyl, 8) optionally substituted dihydrobenzofuranyl, 9) optionally substituted indazolyl, 10) optionally substituted pyrrolopyridinyl, 11) benzisoxazolyl optionally substituted, 12) optionally substituted indolinyl, 13) optionally substituted quinazolinyl, 14) optionally substituted dihydroquinazolinyl, 15) optionally substituted furopyridyl, 16) optionally substituted isoquinolyl, 17) optionally substituted pyrrolopyrimidinyl, 18) optionally substituted tetrahydroquinolyl substituted, 19) optionally substituted tetrahydroindazolyl, 20) optionally substituted tetrahydrocyclopentapyrazolyl, 21) optionally substituted pyrrolyl, 22) optionally substituted imidazolyl, 23) optionally substituted pyrazolyl, 24) optionally substituted thienyl, 25) optionally substituted thiazolyl, 26) optionally substituted triazolyl, 27) optionally substituted pyrimidinyl, 28) optionally substituted pyrazyl, 29) optionally substituted imidazopyridinyl, or 30) optionally substituted pyrrolopyrazyl in R22 are 1 to 3 groups selected from

1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen atom and an amino group optionally substituted with 1 or 2 alkyls,

2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen,

3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino,

4) a cycloalkyl,

5) a halogen,

6) a cyano,

7) an aliphatic heterocyclic group,

8) an aryl optionally substituted with 1 or 2 identical or different groups selected from an alkyl optionally substituted with an alkylsulfonylamino optionally substituted with a halogen and a halogen; a halogen; an alkoxycarbonyl; a methanesulfonylamino; a halomethanesulfonylamino; a methanesulfonylaminocarbonyl; a benzoylaminocarbonyl; a benzenesulfonylaminocarbonyl; a hydroxyoxazolyl; a hydroxyoxadiazolyl; a tetrazolyl; a hydroxyl and an alkoxy optionally substituted with an alkoxy,

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9) a heteroaryl optionally substituted with 1 or 2 identical or different groups selected from a

alkyl, an amino, a halogen and an alkoxy,

10) an aryloxy, and

11) an amino optionally substituted with 1 to 2 groups selected from an alkyl optionally

substituted with an alkoxy and alkylsulfonyl,

12) an alkynyl optionally substituted with a hydroxyl,

13) an aliphatic oxy heterocyclic,

14) an arylcarbamoyl optionally substituted with an alkoxy, and

15) an alkanoyl,

or a pharmaceutically acceptable salt thereof.

(4) The compound according to section (3), wherein the substituents of 1) the optionally substituted aryl, 2) the optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 4) the optionally substituted indole, 5) the optionally substituted benzofuranyl, 6) optionally substituted quinolyl, 7) optionally substituted chromanyl, 8) optionally substituted dihydrobenzofuranyl, 9) optionally substituted indazolyl, 10) optionally substituted pyrrolopyridinyl, 11) optionally substituted benzisoxazolyl, 12) indolinyl optionally substituted, 13) optionally substituted quinazolinyl, 14) optionally substituted dihydroquinazolinyl, 15) optionally substituted furopyridyl, 16) optionally substituted isoquinolyl, 17) optionally substituted pyrrolopyrimidinyl, 18) optionally substituted tetrahydroquinolyl, 19) optionally tetrahydroindazolyl substituted, 20) tetrahydrocyclopentapi optionally substituted razolyl, 21) optionally substituted pyrrolyl, 22) optionally substituted imidazolyl, 23) optionally substituted pyrazolyl, 24) optionally substituted thienyl, 25) optionally substituted thiazolyl, 26) optionally substituted triazolyl, 27) pyrimidinyl optionally substituted, 28) optionally substituted pyrazyl, 29) optionally substituted imidazopyridinyl, or, 30) optionally substituted pyrrolopyrazyl as R22 is a group selected from

1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyls,

2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen, and

3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino, or a group selected from

1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyls,

2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen, and

3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino, and 1 to 2 groups selected from 1 2 3 4 5 6 7 8

1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyls,

2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen,

3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino,

4) a cycloalkyl,

5) a halogen,

6) a cyano,

7) an aliphatic heterocyclic group,

8) an aryl optionally substituted with 1 or 2 same or different groups selected from a

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alkyl optionally substituted with an alkylsulfonylamino optionally substituted with a halogen and a halogen; a halogen; an alkoxycarbonyl; a methanesulfoni lamina; a

halomethanesulfonylamino; a methanesulfonylaminocarbonyl; a benzoylaminocarbonyl; a benzenesulfonylaminocarbonyl; a hydroxoxazolyl; a hydroxyoxadiazolyl; a tetrazolyl; a hydroxyl; and an alkoxy optionally substituted with an alkoxy,

9) a heteroaryl group optionally substituted with the same or different 1 or 2 groups selected from an alkyl group, an amino group and an alkoxy group,

10) an aryloxy,

11) an amino optionally substituted with 1 to 2 groups selected from an alkyl optionally substituted with an alkoxy and alkylsulfonyl,

12) an alkynyl optionally substituted with a hydroxyl,

13) an aliphatic oxy heterocyclic,

14) an arylcarbamoyl optionally substituted with an alkoxy, and

15) an alkanoyl,

or a pharmaceutically acceptable salt thereof.

(5) The compound according to any of sections (1) to (4), wherein R22 is a group selected from

2) optionally substituted pyridyl,

3) the optionally substituted pyrazolopyridyl,

7) optionally substituted chromanyl,

13) the optionally substituted quinazolinyl,

14) the optionally substituted dihydroquinazolinyl,

15) the optionally substituted furopyridyl, and 29) the optionally substituted imidazopyridinyl,

or a pharmaceutically acceptable salt thereof.

(6) The compound according to any one of paragraphs (1) to (5), wherein R22 is a group selected from 16) the optionally substituted isoquinolyl, 17) the optionally substituted pyrrolopyrimidinyl, 18) the optionally substituted tetrahydroquinolyl, 19 ) optionally substituted tetrahydroindazolyl, 20) optionally substituted tetrahydrocyclopentapyrazolyl, 21) optionally substituted pyrrolyl, 22) optionally substituted imidazolyl, 23) optionally substituted pyrazolyl, 24) optionally substituted thienyl, 25) optionally substituted thiazolyl, 26) the optionally substituted triazolyl, 27) the optionally substituted pyrimidinyl, 28) the optionally substituted pyrazyl, and 30) the optionally substituted pyrrolopyrazyl, or a pharmaceutically acceptable salt thereof.

(7) The compound according to section (1), wherein the substituents of 1) the optionally substituted aryl, 2) the optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 4) the optionally substituted indole, 5) the optionally substituted benzofuranyl, 6) optionally substituted quinolyl, 7) optionally substituted chromanyl, 8) optionally substituted dihydrobenzofuranyl, 9) optionally substituted indazolyl, 10) optionally substituted pyrrolopyridinyl, 11) optionally substituted benzisoxazolyl, 12) indolinyl optionally substituted, 13) optionally substituted quinazolinyl, 14) optionally substituted dihydroquinazolinyl, 15) optionally substituted furopyridyl, 16) optionally substituted isoquinolyl, 17) optionally substituted pyrrolopyrimidinyl, 18) optionally substituted tetrahydroquinolyl, 19) optionally tetrahydroindazolyl substituted, 20) tetrahydrocyclopentapi optionally substituted razolyl, 21) optionally substituted pyrrolyl, 22) optionally substituted imidazolyl, 23) optionally substituted pyrazolyl, 24) optionally substituted thienyl, 25) optionally substituted thiazolyl, 26) optionally substituted triazolyl, 27) pyrimidinyl optionally substituted, 28) optionally substituted pyrazyl, 29) optionally substituted imidazopyridinyl, or, 30) optionally substituted pyrrolopyrazyl as R22 is a group selected from

1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyls,

2) an alkenyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2

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alkyls, an aryl, a hydroxyl and a halogen, and

3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino, and a group selected from

1) an aryl optionally substituted with 1 or 2 identical or different groups selected from an alkyl optionally substituted with an alkylsulfonylamino optionally substituted with a halogen and a halogen; a halogen; an alkoxycarbonyl; a methanesulfonylamino; a halomethanesulfonylamino; a methanesulfonylaminocarbonyl; a benzoylaminocarbonyl; a benzenesulfonylaminocarbonyl; a hydroxyoxazolyl; a hydroxyoxadiazolyl; a tetrazolyl; a hydroxyl; and an alkoxy optionally substituted with an alkoxy; Y

2) a heteroaryl optionally substituted with 1 or 2 identical or different groups selected from an alkyl, an amino, a halogen and an alkoxy,

or a pharmaceutically acceptable salt thereof.

(8) The compound according to section (7), wherein R22 is a group selected from

2) an optionally substituted pyridyl, 21) an optionally substituted pyrrolyl, 22) an optionally substituted imidazolyl, 23) an optionally substituted pyrazolyl, 24) an optionally substituted thienyl, 25) an optionally substituted thiazolyl, 26) an optionally substituted triazolyl group, 27) an optionally substituted pyrimidyl, and 28) an optionally substituted pyrazyl, or a pharmaceutically acceptable salt thereof.

(9) A medicament for the treatment and / or prophylaxis of hypertension, heart failure, diabetic nephropathy and the like comprising the compound according to any of paragraphs (1) to (8) or a pharmaceutically acceptable salt thereof. .

(10) Substance of any of (1) to (8) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prophylaxis of hypertension, heart failure or diabetic nephropathy.

The term "alkyl" or "alkoxy" in the present invention is illustrated by a linear or branched chain group having 1 to 10 carbon atoms, and groups having 1 to 6 carbon atoms are preferable, and are Especially preferable are groups having 1 to 4 carbon atoms.

The term "alkenyl" is illustrated by a linear or branched chain group having 2 to 10 carbon atoms, and the group having 3 to 7 carbon atoms is preferable, and the group having 3 to 3 is especially preferable. at 5 carbon atoms.

The term "alkynyl" is illustrated by a linear or branched chain group having 2 to 10 carbon atoms, and the group having 3 to 7 carbon atoms is preferable, and the group having 3 to 3 is especially preferable. at 5 carbon atoms.

The term "alkanoyl" is illustrated by a linear or branched chain group having 1 to 7 carbon atoms, and the group having 2 to 5 carbon atoms is preferable.

The term "cycloalkyl" is illustrated by a cycloalkyl group having 3 to 8 carbon atoms, groups having 3 to 6 carbon atoms are preferable and groups having 3 to 4 carbon atoms are especially preferable.

The term "halogen" is illustrated by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom, a chlorine atom and a bromine atom are preferred, and is especially preferable. a fluorine atom

The term "aryl" is illustrated by a phenyl, a naphthyl and a phenyl is preferable.

The term "heteroaryl" is, for example, an aromatic cyclic group comprising 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, including a monocyclic group having a 5- to 6-membered ring, a group bicyclic of an 8 to 10-membered ring wherein the same or different monocyclic heteroaromatic rings are fused together, and a bicyclic group of an 8 to 10-membered ring in which a monocyclic heteroaromatic ring is fused with a benzene.

The aliphatic heterocyclic ring in the "aliphatic heterocyclic group" and "aliphatic oxy heterocyclic" is illustrated by, for example, a non-aromatic heterocyclic ring comprising 1 to 4 heteroatoms selected from atoms of

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nitrogen, oxygen atoms and sulfur atoms that have 5 to 12 member rings as a whole and that may be totally or partially saturated.

The lower alkyl in R is illustrated, for example, by a straight or branched chain group having 1 to 4 carbon atoms, and a methyl is especially preferable.

As the cycloalkyl of R1, cyclopropyl is preferable.

1) The optionally substituted aryl group, 2) the optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 4) the optionally substituted indole, 5) the optionally substituted benzofuranyl, 6) the optionally substituted quinolyl, 7) the optionally substituted chromanyl, 8) the optionally substituted dihydrobenzofuranyl, 9) the optionally substituted indazolyl, 10) the optionally substituted pyrrolopyridinyl, 11) the optionally substituted benzisoxazolyl, 12) the optionally substituted indolinyl, 13) the optionally substituted quinazolinyl, 14) the optionally substituted dihydroquinazolinyl, 15 ) the optionally substituted furopyridyl, 16) the optionally substituted isoquinolyl, 17) the optionally substituted pyrrolopyrimidinyl, 18) the optionally substituted tetrahydroquinolyl, 19) the optionally substituted tetrahydroindazolyl, 20) the optionally substituted tetrahydrocyclopentapyrazolyl, 21) the optionally substituted pyrrolyl gone, 22) the optionally substituted imidazolyl, 23) the optionally substituted pyrazolyl, 24) the optionally substituted thienyl, 25) the optionally substituted thiazolyl, 26) the optionally substituted triazolyl, 27) the optionally substituted pyrimidinyl, 28) the optionally substituted pyrazyl , 29) the optionally substituted imidazopyridinyl, or, 30) the optionally substituted pyrrolopyrazyl as R22 is preferably a group substituted with 1 to 3 substituents. One of said 1 to 3 substituents is preferably selected from

1) an alkyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, aryl, a hydroxyl and a halogen,

2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen, and

3) an alkoxy optionally substituted with an alkoxy,

and, especially preferably, one of said 1 to 3 substituents is preferably selected from

1) a (C2-4) alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, aryl, hydroxyl and a halogen,

2) a (C2-4) alkenyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, aryl, hydroxyl and a halogen, and

3) an (C2-4) alkoxy optionally substituted with an alkoxy,

especially, one of said 1 to 3 substituents is preferably

a (C2-4) alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, aryl, hydroxyl and a halogen, specifically, one of said 1 to 3 substituents are a (C2-4) alkoxycarbonylamino alkyl.

The compound [I] of the present invention can be used clinically in free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt of compound [I] include a salt with an inorganic acid such as hydrochloride, sulfate, phosphate or hydrobromide, or a salt with an organic acid such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate. In addition, when the compound [I] of the present invention has a substituent such as one or more carboxyl groups, examples of the pharmaceutically acceptable salt include, salts with a base (such as alkali metal such as sodium salt and potassium salt or alkaline earth metal such as calcium salt).

"The compounds described in the Examples" comprise a free form of any compound that is described as a salt form in the Examples.

The compound [I] of the present invention also includes a mixture of a stereoisomer such as a geometric isomer, a tautomer and an enantiomer, and an isolated stereoisomer thereof. In the compound [I] of the present invention, the configuration (R) is preferable for an asymmetric carbon atom of the morpholine ring having the substituent, R6, from the viewpoint of renin inhibition. From the standpoint of renin inhibition, the configuration (R) is also preferable for an asymmetric carbon atom that is

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replaced with R.

The present invention also includes an intramolecular salt, a hydrate, a pharmaceutically acceptable solvate and a crystalline polymorph form of the compound [I]. Additionally, it should be understood that the compound [I] of the present invention is not limited to the compounds described in the following examples, but includes all of the compounds of the formula [I] and the pharmaceutically acceptable salts thereof.

Accordingly, the compound of the present invention or pharmaceutically acceptable salts thereof may be useful as an agent for the prevention and / or treatment of hypertension, heart failure, diabetic nephropathy, and may be advantageous as a medicament due to its low toxicity

The compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be formulated in a conventional pharmaceutical preparation such as tablets, granules, capsules, powders, injectables or inhalants, etc.

The dose of the compound [I] of the present invention or a pharmaceutically acceptable salt thereof may vary according to the routes of administration, and the ages, body weights and conditions of the patients, but usually it is in the range of about 0.001 to 500 mg / kg, preferably in the range of about 0.1 to 100 mg / kg.

The compound [I] of the present invention can be prepared by the following methods, but should not be considered limited thereto.

Method for preparing the compound [I]

The compound [I] of the present invention or the pharmaceutically acceptable salt thereof can be prepared by deprotecting P1 of the compound of the formula [II];

image2

where, P1 is a protecting group and the other symbols are the same as defined above, and converting the product into a pharmaceutically acceptable salt thereof, if necessary.

Method for preparing the compound [II]

The compound [II] can be prepared by reacting a carboxylic compound of the formula [III]:

image3

R6

where the symbols are the same as defined above, or an activated derivative thereof with an amine compound of the formula [IV];

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(R22RCH) R1NH [IV]

where the symbols are the same as defined above.

The compound of the present invention has two or more asymmetric carbons and the reaction product can be obtained as a mixture of diastereoisomers. Said mixture of diastereoisomers can be separated and purified by a usual method, a silica gel column chromatography, for example.

Reaction in the method to prepare the compound [I]

Examples of the protecting group shown as P1 include a usual amino protecting group such as a t-butoxycarbonyl, a benzyloxycarbonyl, a 4-methoxybenzyloxycarbonyl, a benzyl, a 4-methoxybenzyl, an acetyl, a benzoyl, a tosyl.

The protecting group P1 of the compound [II] can be deprotected by treatment with acid or base or catalytic reduction or a deprotection agent in a suitable solvent or without solvent. As for the acid, an inorganic acid such as hydrochloric acid, sulfuric acid and an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid can preferably be used. As for the base, an inorganic base (eg, an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as sodium and potassium carbonate, an alkali metal amide such as such as sodium amide and lithium amide, an alkali metal alkoxide such as sodium methoxide, an alkali metal such as sodium, and an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc.). As for the deprotecting agent, zinc bromide and trimethylsilane trifluoromethanesulfonate, etc. can be used. Catalytic reduction can be carried out preferably using palladium on carbon, palladium hydroxide on carbon, platinum oxide as a catalyst in a hydrogen atmosphere. Examples of the solvent include any solvent that does not alter the reaction, such as methanol, ethanol, isopropyl alcohol, 1,4-dioxane, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, ethyl acetate, toluene and a mixture of the same. The acid or base described above can be used as a solvent. The reaction can be suitably carried out from -78 ° C to the boiling temperature of the solvent.

Reaction in the method to prepare the compound [II]

The compound [II] can be prepared by a condensation reaction of a carboxylic acid compound [III] and an amine compound [IV] in a suitable solvent or without solvent.

The condensation reaction can be carried out by a conventional condensation reaction in the presence of a condensing agent, or by reacting an activated derivative of the compound [III] (eg, an acid halide, a mixed acid anhydride, an activated ester) with the compound [IV], after which the compound [III] becomes the reactive derivative thereof. Examples of the condensing agent include N, N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) or hydrochloride thereof, carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA), diethyl cyanophosphonate (DEPC), and among them DCC, EDC or its hydrochloride is preferable.

When the reactive derivative of compound [III] is used, the reactive derivative can be reacted with the compound [IV] in a suitable solvent or without a solvent in the presence of an acid scavenger if necessary, after the compound [ III] is converted to an acid halide using a halogenating agent (eg, thionyl chloride, thionyl bromide, oxalyl chloride), a mixed acid anhydride using chlorocarbonate ester (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chloroformate) or acid chloride (2,4,6-trichlorobenzoyl chloride), or an activated ester of N-hydroxylamine compound (1-hydroxysuccinimide, 1- hydroxybenzotriazole) or phenol compound (p -nitrophenol) or a lower alcohol ester (methyl ester, ethyl ester). In a method for conversion to an acid halide, the addition of a catalyst such as dimethylformamide can accelerate the reaction. As an acid scavenger, an inorganic base or an organic base is used when necessary, and examples of an inorganic base include sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, Lithium hydroxide and examples of an organic base include triethylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo [5,4,0] undeca-7-ene, N, N-diethylaniline, pyridine, lutidine, collidine. In the present reaction, triethylamine, diisopropylethylamine, pyridine are preferably used as the acid scavenger. When the acid scavenger is used in this reaction, an acid scavenger is used as the solvent.

In the condensation reaction shown above, it can be conducted or accelerated by adding 4- aminopyridine.

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When a solvent is used in the above condensation reaction, any inert solvent that does not alter the reaction can be used and examples of the solvents include chloroform, dichloromethane, dichloroethane, toluene, diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane , ethyl acetate, amide-related solvents (N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone etc.), pyridine, 2,6-lutidine, water, and can also be used A mixture of them. Among them, chloroform, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, and a mixture of chloroform and N, N-dimethylformamide, etc. are preferred.

Usually, the above condensation reaction can be carried out at a temperature of -20 ° C at the reflux temperature of the solvent and, if necessary, can be carried out at a lower temperature that is properly selected.

Examples of the compounds [I] of the present invention prepared by the methods illustrated above are shown below.

Examples

Example 1*

[* The asterisk identifies an example according to the invention]

image4

(1) To a solution of (3- {3 - [(1R) -1- (dclopropylamino) ethyl] -6-methyl-1 H -pyrazolo [3,4-b] pyridin-1-yl} propyl) carbamate of methyl (4.00 g) and (2R, 6S) -4- (tert-butoxycarbonyl) -6- (methoxymethyl) morpholin-2-carboxylic acid (3.66 g) in N, N-dimethylformamide (80 mL) is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.45 g), 1-hydroxybenzotriazole (1.63 g) was added thereto under ice cooling, and then the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 ^ ethyl acetate) to provide (2R, 6S) -2- {cyclopropyl [(1R) -1 - (1- {3 - [(methoxycarbonyl) amino] propyl} -6-methyl-1 H -pyrazolo [3,4-b] pyridin-3-yl) ethyl] carbamoyl} -6- (methoxymethyl) morpholin-4- tert-butyl carboxylate (5.57 g).

APCI-MS m / z: 589 [M + H] +.

(2) To a solution of (2R, 6S) -2- {cyclopropyl [(1R) -1- (1- {3 - [(methoxycarbonyl) amino] propyl} -6-methyl-1H-pyrazolo [3,4 - b] pyridin-3-yl) ethyl] carbamoyl} -6- (methoxymethyl) morphophin-4-carboxylic acid tert-butyl ester (5.28 g) in dichloromethane (30 mL) trifluoroacetic acid (15 mL) was added under cooling with ice and then the mixture was stirred at room temperature for 1 hour. The resulting reaction solution was concentrated under reduced pressure, and chloroform was added to the resulting residue, a saturated aqueous solution of sodium hydrogen carbonate was added to neutralize the mixture under ice cooling, and then the organic layer was separated. The organic layer was washed with saturated saline, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography-NH (eluent: ethyl acetate ^ ethyl acetate / methanol = 20/1) to provide (3- {3 - [(1 R) -1 - (cyclopropyl {[(2R, 6S) -6- (methoxymethyl) morphophin-2-yl] carbonyl} amino) ethyl] -6-methyl-1 H -pyrazolo [3,4-b] pyridin-1-yl} propyl) carbamate methyl (3.72 g).

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APCI-MS m / z: 489 [M + H] +.

Example 2 *

image5

(1) To a solution of (2R, 6S) -4- (tert-butoxycarbonyl) -6- (methoxymethyl) morpholin-2-carboxylic acid (7.59 g) in

Dichloromethane (70 mL) was added diisopropylethylamine (9.60 mL) and diphenyl chlorophosphate (5.71 mL) under ice cooling, and the mixture was stirred after 15 minutes under ice cooling. A solution of methyl (3- {4 - [(1R) -1- (cyclopropylamino) ethyl] -6-methoxypyridin-2-yl} propyl) carbamate (5.65 g) in dichloromethane (20) mL) cooling with ice, and then the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate under ice cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 ^ ethyl acetate) to provide (2R, 6S) -2- {dclopropyl [(1R) -1 - (2-methoxy-6- {3-

Tert-Butyl [(methoxycarbonyl) amino] propyl} pyridin-4-yl) ethyl] carbamoyl} -6- (methoxymethyl) morpholin-4-carboxylate (7.13

g).

APCI-MS m / z: 565 [M + H] +.

(2) To a solution of (2R, 6S) -2- {cidopropyl [(1R) -1- (2-methoxy-6- {3 - [(methoxycarbonyl) amino] propyl} pyridin-4-yl) ethyl] carbamoyl} -6- (methoxymethyl) morpholin-4-carboxylic acid tert-butyl ester (7.13 g) in dichloromethane (50 mL) was added trifluoroacetic acid (25 mL) under ice cooling, and then the mixture was stirred at temperature atmosphere for 1 hour. The resulting reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue, a saturated aqueous solution of sodium hydrogen carbonate was added to neutralize the mixture under ice cooling, and then the organic layer was separated. The organic layer was washed with saturated saline, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography-NH (eluent: ethyl acetate ^ ethyl acetate / methanol = 20/1) to provide (3- {4 - [(1R) -1- (cyclopropyl { [(2R, 6S) -6- (methoxymethyl) morpholin-2-yl] carbonyl} amino) ethyl] -6-methoxypyridin-2-yl} propyl) methyl carbamate (5.40 g).

APCI-MS m / z: 465 [M + H] +.

Example 3 *

image6

(1) To a solution of (2R, 6S) -4- (tert-butoxycarbonyl) -6- (methoxycarbonyl) morpholin-2-carboxylic acid (289 mg) in dichloromethane (20 mL) was added diisopropylamine (523 pL) and diphenyl chlorophosphate (415 pL), under a stream of nitrogen and cooling with ice, and the mixture was stirred for 30 minutes under ice cooling, then a solution of (3- {2-bromo-5) was added thereto - [(1R) -1- (cidopropylamino) ethyl] thiophene-3-

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Four. Five

il} propyl) methyl carbamate (361 mg) in dichloromethane (3 mL), and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 75/25 ^ 40/60) to provide (2S, 6R) -6 - {[(1R) -1- (5-Bromo-4- {3-

[(Methoxycarbonyl) amino] propyl} thiophen-2-yl) ethyl] (cyclopropyl) carbamoyl} 4-tert-butyl and 2-methyl (522 mg) morpholin-2,4-dicarboxylate.

APCI-MS m / z: 632/634 [M + H] +.

(2) To a solution of (2S, 6R) -6 - {[(1R) -1- (5-bromo-4- {3 - [(methoxycarbonyl) amino] propyl} thiophene-2-

il) ethyl] (cyclopropyl) carbamoyl} morpholin-2,4-dicarboxylate of 4-tert-butyl 2-methyl (504 mg) in 1,2-dimethoxyethane (12 mL) was added phenylboronic acid (195 mg), dichlorobis (triphenylphosphine) palladium (II) (56 mg), and an aqueous solution of normal potassium carbonate 2 (1.2 mL) at room temperature, and the mixture was heated at reflux for 3 hours under a stream of nitrogen. The reaction solution was cooled to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was stirred for a while, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70/30 ^ 30/70) to provide (2S, 6R) -6- (cyclopropyl [(1 R) - 1- (4- {3 - [(Methoxycarbonyl) amino] propyl} -5-phenylthiophene-2-yl) ethyl] carbamoyl} 4-tert-butyl morpholin-2,4-dicarboxylate and 2-methyl (307 mg) .

APCI-MS m / z: 630 [M + H] +.

(3) To a solution of (2S, 6R) -6- {cyclopropyl [(1R) -1- (4- {3 - [(methoxycarbonyl) amino] propyl} -5-phenylthiophene-2-

il) ethyl] carbamoyl} morpholin-2,4-dicarboxylate of 4-tert-butyl and 2-methyl (342 mg) in dichloromethane (10 mL) 2,6-lutidine (285 pL) and trimethylsilyl trifluoromethanesulfonate ( 344 pL) dropwise under ice cooling, and under a stream of nitrogen, the mixture was stirred for 30 minutes with ice cooling. To the reaction solution was added methanol and a saturated aqueous solution of sodium hydrogen carbonate under ice cooling, and the mixture was stirred for 30 minutes, and then extracted with chloroform. The organic layer was washed with saturated saline, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was redissolved in the solvent mixture of methanol (20 mL) -water (2 mL), and an appropriate amount of potassium fluoride was added to the mixture, and then the mixture was stirred for 1 hour at room temperature. After distilling the reaction solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 100/0 ^ 94/6) to provide (2S, 6R) -6- {cyclopropyl [(1 R) -1- (4 - {3 - [(methoxycarbonyl) amino] propyl} -5-phenylthiophene-2-

il) ethyl] carbamoyl} methyl morpholin-2-carboxylate (214 mg).

APCI-MS m / z: 530 [M + H] +.

Example 4

image7

(1) To a solution of (2R) -4- (tert-butoxycarbonyl) morpholin-2-carboxylic acid (104 mg) and diisopropylethylamine

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55

(213 gL) in dichloromethane (2.5 mL) was added diphenyl chlorophosphate (131 mg) under ice cooling, and the mixture was stirred for 15 minutes at the same temperature. To the reaction solution was added a solution of methyl (3- {3- [1- (cyclopropylamino) ethyl] -5- (pyridin-2-yl) -1H-pyrazol-1-yl} propyl) carbamate ( 140 mg) in dichloromethane (2.5 mL) under ice cooling, and the mixture was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography-NH (eluent: n-hexane / ethyl acetate = 1/1) to provide (2R) -2- (aclopropyl { (1R) -1- [1- {3 - [(methoxycarbonyl) amino] propyl} -5- (pyridin-2-yl) -1 H -pyrazol-3-yl] ethyl} carbamoyl) morpholin-4-carboxylic acid tert - butyl (104 mg) and (2R) -2- (cidopropyl {(1S) -1- [1- {3 - [(methoxycarbonyl) amino] propyl} -5- (pyridin-2-yl) -1H-pyrazole -3-yl] ethyl} caibamoyl) tert-butyl morpholin-4-carboxylate (110 mg).

APCI-MS m / z: 557 [M + H] +.

(2) To a solution of (2R) -2- (dclopropyl {(1R) -1- [1- {3 - [(methoxycarbonyl) amino] propyl} -5- (pyridin-2-yl) -1H-pyrazole -3-yl] ethyl} carbamoyl) tert-butyl morpholin-4-carboxylate (100 mg) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added at room temperature, and the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated under reduced pressure, the resulting residue was diluted with ethanol and purified with a Waters PoraPak ™ Rxn CX cartridge (strong cation exchange filler) (purification solvent: water ^ ethanol, eluent: ammonia-methanol 1 normal) to provide (3- {3 - [(1R) -1- {cyclopropyl [(2R) -morpholin-2-ylcarbonyl] amino} ethyl] -5- (pyridin-2-yl) -1H-pyrazole-1-yl } propyl) methyl carbamate (77 mg).

APCI-MS m / z: 457 [M + H] +.

(3) Starting from (2R) -2- (cyclopropyl {(1S) -1- [1- {3 - [(methoxycarbonyl) amino] propyl} -5- (pyridin-2-yl) -1H-pyrazole-3 - il] ethyl} carbamoyl) tert-butyl morpholin-4-carboxylate (105 mg) and using a method analogous to the above was obtained (3- {3 - [(1 S) -1 - {cidopropyl [(2R) - morphophin-2-ylcarbonyl] amino} ethyl] -5- (pyridin-2-yl) -1H-pyrazole-

il} propyl) methyl carbamate (81 mg).

APCI-MS m / z: 457 [M + H] +.

Example 5

image8

image9

image10

(1) To a solution of (2R) -2 - [[1R) -1- {1 - [(benzyloxy) methyl] -2- (propan-2-yloxy) -1H-imidazol-4- yl} ethyl] (cidopropyl) carbamoyl} tert-butyl morpholin-4-carboxylate (215 mg) in methanol (6.0 mL), 20% palladium hydroxide on carbon (80 mg) was added, and the mixture was stirred under an atmosphere of hydrogen for 6 hours. 20% Palladium hydroxide on carbon (80 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The insoluble matter was filtered off through Celite, and the filtrate was concentrated under reduced pressure to provide (2R) -2- (cyclopropyl {(1R) -1- [2- (propan-2- yloxy) -1H -imidazol-4-yl] ethyl} carbamoyl) tert-butyl morpholin-4-carboxylate (190 mg).

APCI-MS m / z: 423 [M + H] +.

(2) To a solution of (2R) -2- (cyclopropyl {(1R) -1- [2- (propan-2-yloxy) -1H-imidazol-4-yl] ethyl} carbamoyl) morpholin-4-carboxylate of tert-butyl (185 mg) and methyl (3-bromopropyl) carbamate (215 mg) in N, N-dimethylformamide (4.0 mL) potassium carbonate (242 mg) was added, and then the mixture was stirred at 60 ° C for 17 hours. After cooling the reaction solution, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform ^ chloroform / methanol = 10/1) to provide (2R) -2- (cyclopropyl {(1 R) -1- [1- {3- [(methoxycarbonyl) amino] propyl} -2- (propan-2-yloxy) -1H-imidazol-4-yl] ethyl} carbamoyl) tert-butyl morpholin-4-carboxylate (143 mg).

APCI-MS m / z: 538 [M + H] +.

(3) To a solution of (2R) -2- (cidopropyl {(1R) -1- [1- {3 - [(methoxycarbonyl) amino] propyl} -2- (propan-2-yloxy) -1H- imidazole -4-yl] ethyl} carbamoyl) tert-butyl morpholin-4-carboxylate (140 mg) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL) under ice cooling, and then the mixture was stirred at room temperature for 1 hour. The resulting reaction solution was concentrated under reduced pressure, chloroform was added to the resulting residue, and a saturated aqueous solution of sodium hydrogen carbonate was added.

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to neutralize the mixture by cooling with ice, and then the organic layer was separated. The organic layer was washed with saturated saline, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography-NH (eluent: ethyl acetate ^ ethyl acetate / methanol = 8/1) to provide (3- {4 - [(1R) -1- {aclopropil [ (2R) -morpholin-2-ylcarbonyl] amino} ethyl] -2- (propan-2-yloxy) -1 H -imidazol-1-yl} propyl) methyl carbamate (81 mg).

APCI-MS m / z: 438 [M + H] +.

Example 6

image11

(1) To a solution of (2R) -2 - {[(1R) -1- (2-cyclohexyl-1H-imidazol-4-yl) ethyl] (cidopropyl) carbamoyl} tert-butyl morpholin-4-carboxylate (735 mg) and methyl (3-bromopropyl) carbamate (482 mg) in N, N-dimethylformamide (10 mL) was added potassium carbonate (453 mg), and then the mixture was stirred at 60 ° C for 17 hours. Additional methyl 3-bromopropyl carbamate (964 mg) was added thereto, and the mixture was stirred at 60 ° C for 48 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and then the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was briefly purified by silica gel column chromatography (eluent: chloroform / methanol = 1/0 ^ 19/1), and then purified by gel penetration chromatography (eluent: chloroform) to provide (2R) -2 - {[(1R) -1- (2-Cidohexyl-1- {3- [(methoxycarbonyl) aminopropyl} -1H-imidazol-4-yl) ethyl] (cyclopropyl) carbamoyl} morpholin-4-carboxylate tert -butyl (640 mg).

APCI-MS m / z: 562 [M + H] +.

(2) To a solution of (2R) -2 - {[(1R) -1- (2-cidohexyl-1- {3 - [(methoxycarbonyl) aminopropyl} -1H-imidazol-4- yl) ethyl] (cyclopropyl ) tert-butyl carbamoyl} morpholin-4-carboxylate (630 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (1.5 mL) under ice cooling, and the mixture was stirred for 1 hour at the same temperature. The mixture was concentrated under reduced pressure, and a saturated sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography-NH (eluent: ethyl acetate / methanol = 19/1 ^ 17/3) to provide (3- {2-cyclohexyl-4 - [(1 R) - 1- {cyclopropyl [(2R) -morpholin-2-ylcarbonyl] amino} ethyl] -1H-imidazol-1- yl} propyl) methyl carbamate (410 mg).

APCI-MS m / z: 462 [M + H] +.

[Table 1.]

 Example No.

 Chemical Formula Result MS Method MS Ionic Species

 Example 7

 ch3 Hn S 9Hil Un.n ^ nA0 Oa 414 APCI [M + H] +

 Example 8

 A ch3 414 APCI [M + H] +

 Example 9

   430 APCI [M + H] +

 Example No.

 Chemical Formula Result MS Method MS Ionic Species

 CH3 '°> NH HI¡A 0 chV ° and v to ch3

 Example 10

 a h, nA ch3 A.0 <\ W RAA-AÍ HAV 391 APCI [M + H] +

 Example 11

 QH3 P HN ^ $ ch5Y ° v and k ch3 i N 426 APCI [M + H] +

 Example 12

 c83 «Q, <WIT0 ch3 401 APCI [M + H] +

 Example 13

 ch3-o 's A 9 H tS ^ ñ ch3o 403 APCI [M + H] +

[Table 2.]

 Example 14

 CHjf9 h ^ ¿L N L)) and 1 U-S 0 ch3u 405 APCI [M + H] +

 Example 15

 oH-! Hlp, \? HV ° NlTf0 A ch3 401 APCI [M + H] +

 Example 16

   419 APCI [M + H] +

 CH3 ^ 1 9HW ° 9a F

 Example 17

 ch3-o ■ \. ÍHrS Y rNi ch3o 414 APCI [M + H] +

 Example 18

 ch3 ° \ hijtn 'ClYy-O íXj'po ci A 421/423 APCI [M + H] +

 Example 19

 ch3 S Hlp, S ch5t ° ° and V ^ na ° o'V A 419 APCI [M + H] +

 Example 20

 CH3 ° v H Ai and rNi rVVvV CHjx ^ N qh30 415 APCI [M + H] +

[Table 3.]

 Example 21

 CH3 hn ^ \ chV ° ^ N'V '^ N'T) c% 416 APCI [M + H] +

 Example 22

 CHrV V-, H N-n Y r '^ rvVrV CH30 402 APCI [M + H] +

 Example 23

   405 APCI [M + H] +

 hn ^ Y 9HV ° kTT'í vjy ^; jp.

 Example 24

 C¿¿ HIp ^ c¿r ° nnT | i ° ch3-o 417 APCI [M + H] +

 Example 25

 ch3-q \. cH¡0Yji Y rN "1 ch3o 392 APCI [M + H] +

 Example 26

 chO Vix ch3 401 APCI [M + H] +

 Example 27

 a 0 CH3 h ChkX J CH3 404 APCI [M + H] +

[Table 4.]

 Example 28

 CH3-NH HfO)> NH ChY (S nJn ^ o 7 í W ^ CH3 443 APCI [M + H] +

 Example 29

 CH3-O ^ hn ^ S? HW ° VySA) and ~ \ a chT 444 APCI [M + H] +

 Example 30

   415 APCI [M + H] +

 CH3 ^ Ó-, HN ^ | ^ CHaT0 or A CH3

 Example 31

 CH3 „is hn ^ chVt0 VU A ch3 401 APCI [M + H] +

 Example 32

 ch3 ° "| HN ^ S chV ° ° T nT ^ n ^ ° U A 414 APCI [M + H] +

 Example 33

 -T »V ^ N A ch3 401 APCI [M + H] +

[Table 5.]

 Example 34

 ch3 P HN ^ (CbAr0 / nYt ch3 401 APCI [M + H] +

 Example 35

 chjT Y A cti3 / rrNT cr CH30 429 APCI [M + H] +

 Example 36

 JO ch3 S, ~> i Y rN ') ^ rvvNAj v / CH3O 441 APCI [M + H] +

 Example 37

   429 APCI [M + H] +

 QH3 r ° N ye * CHsV ^

 Example 38

 ch3 P HhT'q (chW ° \ XJ A ch3 429 APCI [M + H] +

 Example 39

 <ttntan: a "or ch3 401 APCI [M + H] +

[Table 6.]

 Example 40

 rH-0 | N-_ H,% Y rN'i cH1rvS'NrLoJ O ^ s-N CH30 431 APCI [M + H] +

 Example 41

 CH3-0 _ X-NH S 9 * V 9Á ch3c> 460 APCI [M + H] +

 Example 42

 QH3.0 CHf HNS H cüknT Y A íVyW CH30 444 APCI [M + H] +

 Example 43

   430 APCI [M + H] +

 CH3 \ 1 D O-f H (S \ ^ yX0J CHgO

 Example 44

 ch3 (° "fP <9HW °" and Yp A ch3 402 APCI [M + H] +

 Example 45

 to! HifX chX ° ° ctf¡CH3 430 APCI [M + H] +

[Table 7.]

 Example 46

 ch3 \ X <YTi 1hA ° ch3 ch3 416 APCI [M + H] +

 Example 47

 ch3 P Hlpl / chX ° 0 XnT to CHg 401 APCI [M + H] +

 Example 48

 ch3 P HN ^ / cX0 A¡Vr (3 N-J '^ Á CHj 400 APCI [M + H] +

 Example 49

   444 APCI [M + H] +

 ch3 0 0 = <NH XjbnP

 Example 50

 ch3 P o = <NH} „H 444 APCI [M + H] +

 Example 51

 </ * »0pHi, and A yVS'NrloJ V = N CH30 431 APCI [M + H] +

[Table 8.]

 Example 52

 , ch3 O Hi Y A) rV'rNrLüJ CHsO 431 APCI [M + H] +

 Example 53

 .ch3 O /,. chJí-n Y A | YyVoJ ch3o 415 APCI [M + H] +

 Example 54

 ch3 0 \ /. ChN-n and rN "! YyYoj s ^ s / ch3o 415 APCI [M + H] +

 Example 55

   445 APCI [M + H] +

 .ch3 0 (__ H o-vii Y r'Y ¿h / Vy'W w ch3o

 Example 56

 CH3 ^ A h>. Y A | yAny ^ ° ^ yN CH30 ch3 415 APCI [M + H] +

 Example 57

 CH5 ° v, H n-n Y rS r "C ^ N y" oj g¿y ch3 ° 431 APCI [M + H] +

[Table 9.]

 Example 58

 ch3 Y-o q - ^ - NH HN "^ AA dfiT 459 APCI [M + H] +

 Example 59

 CHAr VviHX OR A 470 APCI [M + H] +

 Example 60

 ch3-o O ^ NH HNf ^ S CHjr-0 ° Yj ¥ 0 CHsO ^^ A 422 APCI [M + H] +

 Example 61

   390 APCI [M + H] +

 ch3 cyo HN. EYE ch3o

 Example 62

 oK ° 'CH3 NH} „H ch ^ -n Y YS ryS'VV ^ ch3o 444 APCI [M + H] +

 Example 63

 CH3-0 HN ^ ° T ch'vO \ nJ.X N N O PA HO-P 460 APCI [M + H] +

 [Table 10.]

 Example 64

 oCH> (f> «Y A yy-YNrv N« ss / ch3o 431 APCI [M + H] +

 Example 65

 P'CH-i 0 = (3 NH ¿Y A ^ CH30 460 APCI [M + H] +

 Example 66

 OK0 '™ 3 NH <?> ■ «Y A ^ CH3o 460 APCI [M + H] +

 Example 67

   458 APCI [M + H] +

 A ~ <0, FHN-. HN-v VaP u \ _r ~ i or ch3

 Example 68

 CHan HNp N—, QH¡V ^ í ^) ° 'W ~ i ch3 418 APCI [M + H] +

 Example 69

 QH3 ^ S CH ^ f0 ^ 1IVX'N-'T> pA CH3 416 APCI [M + H] +

[Table 11.]

 Example 70

 CH3-O ° \ cP> w ° PN A ch7 445 APCI [M + H] +

 Example 71

 ch3 Y; ■ ^ HN ^? HW ° YTa nA ° r ^ N A 427 APCI [M + H] +

 Example 72

 CH3 Q uki '^ s 0 s cA ° pA F 499 APCI [M + H] +

 Example 73

   430 APCI [M + H] +

 QH3 (° HIP / chV ° / n1'nYX'n ^ o VUn ¿CH3 CH3

 Example 74

 ch3o 0- ^ ° .... \ ...: HINU. \ H QHr \ V AA tXN-iT0 ch3 ° 421 APCI [M + H] +

 Example 75

 QH3n O-f HNK \ -. H Y A rvvw CHgO F 448 APCI [M + H] +

[Table 12.]

 Example 76

 CH3-0 _ A ® f ~ ^ j> A 448 APCI [M + H] +

 Example 77

 QH3, ~ CK HN ^ A-, CH3Y0 ^ nnv ^ n- ^ or 419 APCI [M + H] +

 Example 78

 ch3 S 9HV ° S ^ Y ^ nao V A aCH3 392 APCI [M + H] +

 Example 79

 , CH3 0 3 ^ 11 ^ _ H Cíi and A rvYN / oj \ ^ = N CH30 429 APCI [M + H] +

 Example 80

 oCHs>) H, NT AND A fWvv CH30 402 APCI [M + H] +

 Example 81

 NH GH3 / H Zjh * Y A frS'NrloJ ^ ch3o 474 APCI [M + H] +

 [Table 13.]

 Example 82

 CH ^ r HQ a, chVu 471 APCI [M + H] +

 Example 83

 aHs hn ^ S 9HV / Yt nao yLn ^ hn- 'o \ ch3u 502 APCI [M + H] +

 Example 84

 ch3 CK ° Kih / H n-, Y Y rVVW CH30 431 APCI [M + H] +

image12

[Table 14.]

 Example 87

 ch3 cyo HIsL 1 „H CH (p-N Y c% A> yíírC0J ch3o 421 APCI [M + H] +

 Example 88

 ch3 cl S „H ch3 r i Y r" i ch3o 377 APCI [M + H] +

 Example 89

 CH3-0 O ^ NH HN ^ i 1 * 9HV ° PA ch3- / 459 APCI [M + H] +

 Example 90

 ch3.0 Cr'NH HN'p S 9HV ° p A CH3 CH3 473 APCI [M + H] +

image13

[Table 15.]

 Example 92

 ch3 óyo HN 1 H fS Y r'S ch3o 408 APCI [M + H] +

 Example 93

 .ch3 0 í 7. cfv ^ n ch3o 416 APCI [M + H] +

 Example 94

 9, Hs HN "^ CHV ° n to o- 'CH3 459 APCI [M + H] +

 Example 95

 ch3 ° Y ° hn. 9 H ch3-0 ~ sX Y rNi ch3o 436 APCI [M + H] +

 Example 96

   434 APCI [M + H] +

image14

[Table 16.]

 Example 97

 CH3-0 Cr NH S chV ° W'N ^ o V A ch3 405 APCI [M + H] +

 Example 98

 ch3 0 Cr'NH HN "^ S 9HV ° V to Cl 425/427 APCI [M + H] +

 Example 99

 ch3.0 O ^ NH HN ^ l chW ° Yy ^ 0 I ^ CH3 ch3 433 APCI [M + H] +

 Example 100

 CH3-0 HN ^ n o ^ r cfC ch3 r "Nt / ch3 488 APCI [M + H] +

 Example 101

 PH3 0 H3CV-QL / N1 Y f] rvWoj CH, 0 445 APCI [M + H] +

[Table 17.]

 Example 102

 ch3 | P ck NH} „H 7 * 1 Y rN'i oh CH3H« n ch3o 445 APCI [M + H] +

 Example 103

 CH ^ ° V H ch ^ nÍ6h3o 416 APCI [M + H] +

 Example 104

 CH3'i. hn ^ ° T chV u k 447 APCI [M + H] +

 Examples 105

 ch3.0 O ^ NH HN ^ S cA ° ch3 475 APCI [M + H] +

 Example 106

 ch3 ÓyO HNL ch3o 434 APCI [M + H] +

[Table 18.]

 Example 107

   448 APCI [M + H] +

 ch3 me HN. CVV * I AND A ÍMW ch3o

 Example 108

 CH ^ h hO S A / yV '? 0 A ch3 429 APCI [M + H] +

 Example 109

 ch3.0 O ^ NH HN ^ S chV0 ° YVn \ Y A Ch3 421 APCI [M + H] +

 Example 110

 ch3 ° -i hn "Y 1 A ° Yr r ° i ^ ch3 CH3 404 APCI [M + H] +

 Example 111

 CHg-0 _ ChO M A CH3W Yn- / ch3 487 APCI [M + H] +

[Table 19.]

 Example 112

 ch3 S chW0 StV ^ nAo Y at xh3 390 APCI [M + H] +

 Example 113

   415 APCI [M + H] +

 C \ H3 HN— "| cnV0 Wro A ch3 ¿h3

 Example 114

 ch3-o - 0 ^ NH HpQ S 9HV 1nV'nao pk 508/510 APCI [M + H] +

 Example 115

 , ch3} CH * k, V JL O'X vi T [I fVVW CH30 445 APCI [M + H] +

 Example 116

 HN ^ \ chW ° U ^ N ¿ctíT 415 APCI [M + H] +

 Example 117

 oHs HN ~ - | \ CH5r ° v and A ch3 429 APCI [M + H] +

[Table 20.]

 Example 118

 CH3 chW ° / 'yV'n'S) ch3 \ A ^ N A 431 APCI [M + H] +

 Example 119

   441 APCI [M + H] +

 ch3 "0 JL Cj NH HN" ~ P ^ chW'0 rrN ^

 Example 120

 ch3 or 0 ~ Í HN- \ HN ^ ^ Q O-K ch3> n CH3 419 APCI [M + H] +

 Example 121

 c <& °. Ts HN-X O W N-C o- \ V-i 0 dH 3Vn ch3 421 APCI [M + H] +

 Example 122

 CH3 0 HN- \ oA y \ {and HNA_ ^ ^ Vo ^ v_ uA xVi 0 ry ~ H ch3 445 APCI [M + H] +

 Example 123

 <[O> = \ N- </ —C i 0 {^ J- N CH3 416 APCI [M + H] +

 Example 124

 pn íü? hn ^ ChA'0 VV A CH3 CH3 429 APCI [M + H] +

[Table 21.]

 Example 125

   415 APCI [M + H] +

 S 3? / YV'ro ch3

 Example 126

 ch3 S chVt0 CH3jOíA¡i ‘0 TO 390 APCI [M + H] +

 Example 127

 CH3-0 HN ^ S chW- ° Sf ^ T 0 Y A xh3 376 APCI [M + H] +

 Example 128

 CH —0 Jl Cr "NH HN ^ Y 1 At ° Yrr ° A 467 APCI [M + H] +

 Example 129

 CH3-O HNv ^ D YYf A 431 APCI [M + H] +

 Example 130

 “Y cP> / n-txanao W A CHg Cl 449/451 APCI [M + H] +

[Table 22.]

 Example 131

   429 APCI [M + H] +

 oh4 hO / VY ^ nao OJ A CH ^ CHs

 Example 132

 code> iW'KTI CLI A 427 APCI [M + H] +

 Example 133

 QH3o 0-f HN-. H ^ H3 ° 431 APCI [M + H] +

 Example 134

 ch3 hn ^ ÓV chV0 '-N-Vl 0 CH3-0 A NK 415 APCI [M + H] +

 Example 135

 CH3-O ^ o ^ T A "Q> S? T 1'N'Vanao HA r ~ N ch3 444 APCI [M + H] +

 Example 136

 CH3'0 O ^ NH HN ^ 1 y ^ N u A v> 456 APCI [M + H] +

[Table 23.]

 Example 137

   459 APCI [M + H] +

 CH3 — O Cr "NH HIsT ^ i L? HW ° YySao A

 Example 138

 CHg-0. A-nh HfTX s ^ nV'n '^ or N- * 444 APCI [M + H] +

 Example 139

 CH, -0 ^ S? HV mn ^ F 448 APCI [M + H] +

 Example 140

 QH3 (° Hlí ^ <cnW ° / nYt nao VM A CHsXCH3 429 APCI [M + H] +

 Example 141

 CH3-0 T O ^ NH HN ^] VA «v ^ CH3-cr ^ 471 APCI [M + H] +

 Example 142

 CH3-O Cr'NH l CH ^ ° Wo ju N ^ 459 APCI [M + H] +

 [Table 24.]

 Example 143

   477 APCI [M + H] +

 ch3.0 CfSsIH HN ^) VA F

 Example 144

 CH3 '~ 0 O ^ NH HN ^] S cfiV0 A ^ n ¿oV ^ 455 APCI [M + H] +

 Example 145

 ch3 cyo FIN. (NXx Y1N) ch3o 441 APCI [M + H] +

 Example 146

 CH3-0 Cr'NH HN '* vi L ChLÍ ° STt N ^ O, VA 466 APCI [M + H] +

 Example 147

 chW ° Arvy ° VJI N ^ xh3 433 APCI [M + H] +

[Table 25.]

 Example 148

 chVt0 do irvSAb A ch3 419 APCI [M + H] +

 Example 149

   441 APCI [M + H] +

 ° Y ° -ch3 .NH r „H fYi Y fNl ch3o

 Example 150

 ch3 ° \ CHg ti 440 APCI [M + H] +

 Example 151

 , ch3 ° ym hn ^ 0 S 9HW ° XXJ A cnri ^ ch3 445 APCI [M + H] +

 Example 152

 ch3 S hn ^ S CHV °, nyVn \ VJLn ¿ch3- 'l ch3 443 APCI [M + H] +

 Example 153

 ch3 Á Híf ^ (chW ° W A 0J vk ^ ch3 ch3 ch3 473 APCI [M + H] +

[Table 26.]

image15

 ch3 <? hV VM ^ F L ch3

 Example 156

 ch3 T 0 NH HN '^ i L 9H * Í ° Yrp CH3 l | fN A w 455 APCI [M + H] +

 Example 157

 í C / MH HN '^^ i> chVt'0 yV'ro ch3 i | fN A 441 APCI [M + H] +

 Example 158

 CH3-0 qAnh hiAA S K, 9HV 0 F 474 APCI [M + H] +

 Example 159

 CH3-o ^ 0 <V HIQ) S chV ° VySA) \ J 456 APCI [M + H] +

 Example 160

 óí np \ ^ xk0 <JN A 427 APCI [M + H] +

 Example 161

 ch3 ° n HN ^ S chW ° jX, N ¿ch3 440 APCI [M + H] +

 Example 162

 ch3 0 ^ NH f H cj ± HXíLn CH30 473 APCI [M + H] +

 Example 163

 ^ ■ 0 HN ^ ch3 ^ nh chV ° and ¡° 9 ch3 470 APCI [M + H] +

[Table 28.]

image16

 Example 165

 CH3-0 H! ^> NH CH¿Y "° Vr 474 APCI [M + H] +

 Example 166

 GH3 Q 0-fu HN-, H N- <JL 0 CH® CHr \ = / | jh3 ° 473 APCI [M + H] +

 Example 167

 ch3 ^ ■ 0 Cr'NH HN '"' '"] \ x5! 0 yf * r ° CrN A 431 APCI [M + H] +

 Example 168

 ^ 0 hO CHa> ~ NH CH> r0 v% V'p> J / * 1 A Of 474 APCI [M + H] +

[Table 29.]

 Example 169

 CHy ™ hn ^ a S? HV / J = N A O'01 490/492 APCI [M + H] +

 Example 170

 CH-o ^ 0 X 3? 'n "V'NA0 and A Cl 490/492 APCI [M + H] +

 Example 171

 CH3 - q O ^ -NH Lo N ^ O> A y) F 474 APCI [M + H] +

 Example 172

 CH3-0 HN ^ | > -nh chV ° ^ yr ° and at Q F 474 APCI [M + H] +

 Example 173

 CH3-O VL K? V '-nnVJ'N'Sd 474 APCI [M + H] +

[Table 30.]

 Example 174

 PH-q hO 3> ~ NH CHV0 0 Jr A ►yi ch3- <) 487 APCI [M + H] +

 Example 175

 CH3-0 _ 0 T S1 J = N A M C! 490/492 APCI [M + H] +

 Example 176

 CVnh 9hV ° A A Q ch3 471 APCI [M + H] +

 Example 177

 n HN '"A chtmh oV3 0 A A F 475 APCI [M + H] +

 Example 178

 chAnh hiO, S <fA ch3 470 APCI [M + H] +

[Table 31.]

 Example 179

 CH3- ~ o cHhC ° ^ n'V ^ n'x) rtN A 470 APCI [M + H] +

 Example 180

 CHg-'O 0 ^ NH HN- ^ S CHVO AV * Nt0 rC A u ch3 471 APCI [M + H] +

 Example 181

 XNH HffA S chV ° Va ch3V “N A CH3 422 APCI [M + H] +

 Example 182

 HtvfA CH3-0 _Lx>> -nh 9Hn or v— \ N- ^ n ^ O \ _ ¿T i nJ A Ó 456 APCI [M + H] +

456

APCI

[M + H] +

image17

 Example 184

 CH3-0 'O ^ NH Hísr \ \ N iV ° W, N ^ or Q> ch3 471 APCI [M + H] +

 Example 185

 ch3> nh chW ° FV- <“or * 475 APCI [M + H] +

 Example 186

 n HN ^ i ch *> nh ohW0 Jr A \ -N 457 APCI [M + H] +

 Example 187

 ^, - '0 CH3> NH CHV ° ^ -nnTAn' ^ ° Cüi <r ^ O1 471 APCI [M + H] +

 Example 188

 ch3 p Q = <Kih ¿„H CHs / '- N Y r'S chYi i ° j 4 CH30 422 APCI [M + H] +

 Example 189

 QH3 ok ° m> N AND rN. ch3o 434 APCI [M + H] +

 Example 190

 ch3 0K ° jsllH / H N-n Y YS ovw ch3o 420 APCI [M + H] +

 Example 191

 ch3 \ 3 0 O ^ NH HN- \ CH3W-N "i CH-, ch ^ h3 436 APCI [M + H] +

 Example 192

 chY> ~ nh chC ° -A or 474 APCI [M + H] +

 Example 193

 ch3> -nh F chV0 <fA 474 APCI [M + H] +

[Table 34.] [* The asterisk identifies an example according to the invention]

 Example 194

   431 APCI [M + H] +

 HN ^ "} Y CH3Y0 / => N Á

 Example 195

 QH3 ° Y% HN'P chW'0 d "A 461 APCI [M + H] +

 Example 196 *

 c5h3 humem ^ o '^ CH ^ ° / n'Y "t'nAo VA ^ n ¿CH3 459 APCI [M + H] +

 Example 197

 ch3-o _ chCo 0 \ J 472 APCI [M + H] +

 Example 198

 CHS_0 ^: or ywQ> O 474 APCI [M + H] +

 Example 199

 CH3-0 ^ Hrí * pl VF 9HV ° Vy ^ N ^ o O 474 APCI [M + H] +

 [Table 35.]

 Example 200

   411 APCI [M + H] +

 CH3. HlvT-, \ Chtar0 L'N ^ Vanao / K N A

 Example 201 *

 € H3 _ á-0 H ch3o 400 APCI [M + H] +

 Example 202 *

 O HN ^ YCHa cnr ^ H U> you V 3I and * a or 470 APCI [M + H] +

 Example 203

 ch3-o hn ^ f oMh ch¿t '° JVn or 524 APCI [M + H] +

 Example 204

 p-CH3 or hO and cHy> A O 461 APCI [M + H] +

 Example 205

 Qh3 "fl ° ^ _? HH vNysyo or 428 APCI [M + H] +

 [Table 36.]

 Example 206

   473 APCI [M + H] +

 CH3 'SQ and CT "NH HN ^ | S or 9HV ° V / ro ~ r * A

 Example 207

 chW ° dKA 515 APCI [M + H] +

 Example 208

 CH 3-0 _ ¿T, SD ° 'fsVí'N ^ O N-N 1 or A 458 APCI [M + H] +

 Example 209

 0 ^ ° ‘CH3 NH („ H V V7 N s ~ N ^ X I í) ch3 n ^ yn ^ o ^ ch3o 408 APCI [M + H] +

 Example 210

 0 ^ ° 'CH3 NH oVA) ch3o 462 APCI [M + H] +

[Table 37.]

 Example 211

 0 ^ ° ‘ch3 NH Q-bJrO F ch3o 474 APCI [M + H] +

 Example 212

   354 APCI [M + H] +

 rCHu «iTTi ^ íN1 ^ L'ní; JVny ^ '0'J ch3o

 Example 213

 ch3 ~ o a ^ nh HIQ> S chVu n-n A ch37 <A CH3 CHg 436 APCI [M + H] +

 Example 214

 Sj'VAnao> n A or 449 APCI [M + H] +

 Example 215

 gh3o _ hO S AHT CHj ^ N ¿ch3 ch3 436 APCI [M + H] +

 Example 216

 CHg-O _ OHpo VySA) / = A F A 475 APCI [M + H] +

[Table 38.]

 Example 217

 CH3-O _> NH HOn ^ chW ° Ny ^ M Ad Ah a {ji ch3 485 APCI [M + H] +

 Example 218

 ch3-o _ Hnh HrQ S 9HAf WNyANA0> A \ J 473 APCI [M + H] +

524

APCI

[M + H] +

image18

[Table 39.]

 Example 222

 0 ^ ° 'CH3 NH („H / - \> s Y A \ Vn 1 J, 1 J CH3 ch3o 470 APCI [M + H] +

 Example 223

 ch3 ^ o _ Q ^ NH hi¡Ol S 9HV '-NNyAN' ^ 0 ¿r A yj * ch3 489 APCI [M + H] +

 Example 224

 ch3o ^ HOo S? hH VrA vs A 396 APCI [M + H] +

 Example 225

   422 APCI [M + H] +

 CH3Q ^ qJ'-nh Hpn Y? HÍ N-N X CH3 <& ch3

 Example 226

 ch3-o _ O ^ H "O S chVu ° i ^ n ch3 487 APCI [M + H] +

 Example 227

 CH30 _ O ^ NH HfQ) S chV ° A V / 473 APCI [M + H] +

 Example 228

 ch3-o _ Vi ° Vn ch3 487 APCI [M + H] +

 Example 229

 ch3-o _ CHp VAro O 3 ^ 490 APCI [M + H] +

 Example 230 *

 CH; -0 HN ^ VCH3 0> ~ NH CHV5 \ Vfo> N A O 470 APCI [M + H] +

 Example 231

 ch3 * o ^ O ^ NH VA 0 “A ch3 470 APCI [M + H] +

[Table 41.]

image19

 Examples 233

 CH3-0 _ 0Uh HOn S 9HT CH> 0 TO 448 APCI [M + H] +

 Example 234

 CH30 _> NH HI¡U S 9HT fp = f A CH3 489 APCI [M + H] +

 Example 235

 ch3-o ^ 0 A F 491 APCI [M + H] +

 Example 236

 CH3O _ s QhA-s Cn 487 APCI [M + H] +

[Table 42.]

 Example 237

 CH3-o O ^ NH HN ^ s íh ^ c ° Yrro V A ch3 435 APCI [M + H] +

 Example 238 *

 ch3 0 O ^ NH HN ^ YCH3 A ChW ° Wn ^ O V A ° 'CH3 435 APCI [M + H] +

 Example 239 *

 F CH3-Q ^ i V-NH H ^ F S chV ° ^ Vn ^ o \ j ^ ChT 513 APCI [M + H] +

 Example 240

 CH3'0 Al o »yi ° ch3-n J N 476 APCI [M + H] +

 Example 241

 CH3-0 hO S chVu CH VV '^ O 3-N-TS A N <J 476 APCI [M + H] +

[Table 43.]

 Example 242

 0> HQ) ^ chVu J "s A N> W 474 APCI [M + H] +

 Example 243

 ok ° 'CH3 Kih \ H 0 "CH3 CH3O 486 APCI [M + H] +

 Example 244

 ch3o hn ^ -i o ^ TL í C% ° wr ^ r ° ~ y * a <3 474 APCI [M + H] +

 Example 245 *

 CH3-o „V HN ^ CH3 Anh hi? X 0 s cHk ch3 ^ = N ^ ch3 436 APCI [M + H] +

 Example 246

 ch3-o _ 0> T 0 F 464 APCI [M + H] +

[Table 44.]

 Example 247

 cn3.o ^ NNr ^ N '** 0 J ~ N A i) ch3 471 APCI [M + H] +

 Example 248

 OHs-o ^> NH "fl °> -, chW ° '~~ N N''X" N ^' 0 rCN Á V / 'CH ;. 471 APCI [M + H] +

 Example 249 *

 ch3 ch3-o hyS X ~ NH CHXr0 ^ «Vr ° ch3 459 APCI [M + H] +

 Example 250 *

 ok ° 'CH3 Kih N-n Y ^ cH <TvNrl'oXcH3 CH3W CH30 459 ESI [M + H] +

image20

[Table 45.]

 Example 252 *

 CH, F c 0 ^ L- F 0 ^ l 0 ^ chYu O ^ 498 APCI [M + H] +

 Example 253 *

 oY ™ 3 NH / \ w, N-S Y A H CH3Q q 578 APCI [M + H] +

 Example 254 *

 ok ° 'CH3 NH (H Jt-N Y j'N'¡ J, VvNrloJYacH1 ch3 w ch3o 0 503 APCI [M + H] +

 Example 255 *

 ch3 _ _ ^ Q HN oY chV \ n / n ^ o) = \ A V ch3 475 APCI [M + H] +

 Example 256 *

 P'Ch3 0 = <J Jm-N Y TV ^ yVVcH, CH3 r ’~ CH3O 0 516 APCI [M + H] +

 Example 257 *

 jO ch3-o I Wo ar 565 APCI [M + H] +

 Example 258 *

 CH30 I ™ chV ° Xv-nX t) \ A \\ // ch¡ 475 APCI [M + H] +

 Example 259 *

 0 = <° 'CH3 NH c * _ H N-isi Y rN ch3 w CH3q or 502 APCI [M + H] +

 Example 260

 nil ^ HN''Ssi CH3-O 1 0> -NH ChV 0 Ppl 0 fvQ F VQ 0 CH3 598 ESI [M + H] +

 Example 261 *

 ch3 ch3-o q ^ -NH HN "V S m pAr 0 NP A ch7 489 APCI [M + H] +

 Example 262

 CH3-0 _ O ^ NH Hif ^ l \ IHU 0 F OCH3 598 APCI [M + H] +

 Example 263

 CH3-0 HnT's | 0> ~ | sjH ChW ° ~ y1 to 0) r-NH N Ñ N 540 ESI [M + H] +

 Example 264

 CH3 "0 0> ~ NH CHJr * ° yr Cr0H 488 ESI [M + H] +

 Example 265 *

 CH3-0 X J ~ nh HlíA X? HV ° 0 ^ ch7 477 APCI [M + H] +

 Example 266 *

 ch ^ Q ch3 cAmH HN ^ S S 9 ^ ° STt iñao V A CHJ ° 435 APCI [M + H] +

 Example 267

 ch3-o> NH Hl¡n s VrA O ^ N = (nnnh 540 ESI [M + H] +

 Example 268

 CH3 ^ q HN ^ q> -NH ChVt ° V-ZO'CHg 530 APCI [M + H] +

 Example 269

 ch3 0 CANH HN'A s? hW ° Vrro / = KS ^ \ _ / ~ N4o u CH3 565 APCI [M + H] +

 Example 270

 CHs'0 HfO> -NH CHJf0 ^ V'N '^ O Vs k _f i-A r \ .n ... X_j ^ í JN ^ n-n 540 ESI [M + H] +

 Example 271 *

 pm ch3 0 í CPNH HNI-S S chV VyA V A CH'3 ° 465 ESI [M + H] +

[Table 49.]

 Example 272

   478 ESI [M + H] +

 CH -, - 0 Hlp, 0- ^ nh chW ° 1 * y) 's A Ñ-NH

 Example 273

 P'CH, 0 = <3 Kih <H N * m Y f'NY ^ O '^ GH. mvv CIVO * ^ CH30 503 APCI [M + H] +

 Example 274

 ch3—0 HN ^, 0> ~ NH ChV °> s A <Y ° h 506 APCI [M + H] +

 Example 275

 Chl3-0 HN ^ q ^ NH ChW ° 0 F <V ° H F 524 APCI [M + H] +

 Example 276

 CHg-O HríJ ^ 0 ^ ÑH CHjr0 Ovvo N'NH 556 ESI [M + H] +

[Table 50.]

image21

 Example 278 *

 f ° CH3'0 hn ^ cM "íhV5 VnnYAna ° A \ J \ Jí7 ■■ ch3 557 ESI [M + H] +

 Example 279 *

 ch3 CH3 '° u xó q - ^ - nh Hlí A S? hH / == / = N A v> F 518 ESI [M + H] +

 Example 280 *

 ch3 No O ^ NH H0 s and V * ln "V ^ n ^ or Xa F 488 ESI [M + H] +

[Table 51.]

 Example 281

 CH3 '° ^ O ^ NH H0, ^ chW ° d ^ v ° H O-N 555 APCI [M + H] +

 Example 282 *

 ch3] lHU / J ^ N A y) F 488 ESI [M + H] +

 Example 283 *

 9H3 CHb r ° “O) Y chVu N-N I 0 500 ESI [M + H] +

 Example 284

 CH3-0 Hfíl ^ l 0> ~ NH ChVt''0 0 v / TÍN-a _ ÓKf F F 633 ESI [M + H] +

 Example 285 *

 CHo \ d A 500 ESI [M + H] +

[Table 52.]

 Example 286

 CH3-O 0> ~ NH CHY ° Ot ^ f F 647 ESI [M + H] +

 Example 287

 ch3 ^ d 0 O ^ NH HN ^ 1 IH ^ I ° SdT "NA0 N A / == (or 0 \> - f or w HN'S'0 ch3 593 APCI [M + H] +

 Example 288

 ch3 '0 O ^ NH HN ^ | ^ chW ° VrVo rh> A 655 APCI [M + H] +

 Example 289 *

 ch3q jT ° 'ch3 ° ^ £ HV cf 506 ESI [M + H] +

[Table 53.]

 Example 290 *

 CH3 0'CH3 0 ^ chCí ‘-N'V ^ N ^ O Á w 506 ESI [M + H] +

 Example 291

 CHa-o ^ 3? cfA 464 ESI [M + H] +

 Example 292 *

 ch30 9'CH3 ^ n'Y ^ n- ^ o O A 474 APCI [M + H] +

 Example 293 *

 ex0 ™ »NH ((H n-n Y rY CH CH ¡V CH30 503 ESI [M + H] +

image22

[Table 54.]

 Example 295 *

 ch3 ch3-o r ° J-nh H! i! At 0 C chV ° ^ 'N'V ^ N' ^ O O ^ 474 APCI [M + H] +

 Example 296 *

 / r-, H v »Y rS r \ ^ S'TNY ^ 0 '^ VCH3 NjsSV-n ch3o N n‘N H 529 APCI [M + H] +

 Example 297

 CH3 ’O O ^ NH HN" "^> chW'0 VvV ° / K ^ / ~ NH F O ^ S.-f-F 0 F 619 APCI [M + H] +

 Example 298

 ch3 0 CT'NH> ChW'0 V A JO ch3 422 APCI [M + H] +

 Example 299 *

 CH3 'or JL O ^ NH Hlpn o-y 584 ESI [M + H] +

 Example 300 *

 ch3 ctN í Tnh hij ^ S \ 9HV N-N A ch4h3 466 ESI [M + H] +

 Example 301 *

 Ch3_0 O ^ -NH HN ^ O-CH3 S iHí Yes5> ^ n or N-N Á ch3 466 ESI [M + H] +

 Example 302 *

 ch3 JÓ CH3o f o ^ m "JO, u C chW ° N-N A O A 508 ESI [M + H] +

 Example 303 *

 0 "CH3 CHj-0 _ J O ^ NH Hfj S 9H> 1 Yr» ii WN‘N A O 508 ESI [M + H] +

[Table 56.]

 Example 304 *

   436 APCI [M + H] +

 ch3 1 * 0 X Y A CH3Q - ^^ YNT ° 'A> ^ 0'CH3 ch3o

 Example 305 *

 ok ° 'CHí Jmh n-n Y rN> ^ YF JlVvNrLoJ f GtV ^ ch30 509 APCI [M + H] +

 Example 306 *

   485 APCI [M + H] +

 Example 307 *

 ck0 ™ 3 NH} H n-n V rNY ^ YF f chX ^ ch3o 509 APCI [M + H] +

 Example 308 *

 ch3 'O OH O ^ NH HN' ^ Y ^ X cAy ° Vy1 ^ 0 V A yO cX 451 ESI [M + H] +

[Table 57.]

image23

 Example 310 *

 q.ch3 0-ch3 O ^ NH HN-'V S chV ° ch3 XJ A 0 N A 465 ESI [M + H] +

 Example 311 *

 CH3 jHz '0 0 CT'NH HN' ^ Y ^ A cAv0 VrV * 0 V A jo ch3 479 APCI [M + H] +

 Example 312 *

 QHa cr J • CHJO HN'V or ^ ÍL SY V.NNyAN '\) ch3 503 APCI [M + H] +

 Example 313

 CHg o ^ ° ^ NA chO O-o ^ A 472 APCI [M + H] +

[Table 58.]

 Example 314 *

 ch3 "0 F CT ^ NH HN '^ xf S chW-0 V / r ° NV A ch3 ° 453 ESI [M + H] +

 Example 315

 0'CH3 O ^ NH HN ^ ^ chJt0 YYt 0 CH3 ^ V A ch3 433 ESI [M + H] +

 Example 316 *

 CH »N fe] cAnH HN '^ T l 9HV ° VvNAo V A / O ch3 460 ESI [M + H] +

 Example 317

 0'CH3 GANH HN ^ | i ck ° VYf ° r ^ r N A 475 ESI [M + H] +

 Example 318 *

 CH30 jA or> hO S íHu rf A 0 -s 528 ESI [M + H] +

[Table 59.]

 Example 319

 ‘NH« f N-, V f ^ nVy (0) ch3o 448 APCI [M + H] +

 Example 320 *

 OK0'CH = NH} ^ H FHAv * '<AacH, ch3o 492 APCI [M + H] +

 Example 321 *

 CH3 ^ or CH3n.CH3 0ANH HN '^ V S chVó Vrf or V A CHá0 478 ESI [M + H] +

 Example 322 *

 ch, 0 ra ° H * ch6 A 508 ESI [M + H] +

 Example 323 *

 Yü'ch3 ch3o I 3 chV LnWo rV A o- / 508 ESI [M + H] +

[Table 60.]

 Example 324 *

 uYaCH3 HISL Ay A F CH30 503 APCI [M + H] +

 Example 325

 UYaCH3 HN'l nX Y A Y ^ vVV h F CH30 459 APCI [M + H] +

 Example 326

 CHs'cQ. cp> a ch3 438 APCI [M + H] +

 Example 327 *

 ch3 ~ o jf CHs HfQ> s chV ^ 1nVnao Wi A () ch3 or S 522 ESI [M + H] +

 Example 328 *

   526 ESI [M + H] +

image24

[Table 61.]

 Example 329 *

 CH3 \ r> qjCHJ 7 ChA-O VvyC j A ch3 463 APCI [M + H] +

 Example 330 *

 CH3'iNH m ^ oCH * ° ^ chV F A 0- / 526 ESI [M + H] +

 Example 331 *

 9H3 ch3 \ 0 Jl S 9HV SV-N ^ O ch3> = / i Ko A ch3 482 APCI [M + H] +

 Example 332 *

 or ^ ° 'ch = r. > n Y rV ^ CH'tiA'VV ch3 CH30 491 APCI [M + H] +

 Example 333 *

 CHs'0 ^ ru 0 ^ cL ° or A 476 APCI [M + H] +

[Table 62.]

 Example 334 *

 cr4 ^ H3CO H¡fV>! ^ H ChV3> N A ck 570 APCI [M + H] +

 Example 335 *

 ch3 u rn HN '' ^> -NH CHVU 0 or ^ 476 APCI [M + H] +

 Example 336 *

 jui; h3 u m HN'S 30V yr c & r A ch3 482 APCI [M + H] +

 Example 337 *

 UCH3 h3C0 hnV Vnh chV ° 0 \ aVo J \ A [m CH3 515 APCI [M + H] +

 Example 338 *

 XJüH3 HsCQ HfO) crt, níhÍ WfO and \ a CNCH * 515 APCI [M + H] +

 [Table 63.]

 Example 339 *

   584 ESI [M + H] +

 Q and H3CQ HtfY -HSIH CHVU 0 VM Vn A d o-1

 Example 340 *

 j h3co HfT¿ cHíi 9HV n-n ¿d o-7 496 ESI [M + H] +

 Example 341 *

 t H3cq Hn rftL 7 0 C ^ TN ^ ch3 484 ESI [M + H] +

[Table 64.]

 Example No.

 Salt chemical formula Result MS ESI Ionic Species

 Example 342 *

 CyOCH3 JSIH ^ A r7 ^^ XNT ° ^ ch3 ch3o 2HCl 445.3 [M + H] +

 Example 3 4 3

 ch3 OK ° m rJ ** Y A W fYNfoJ CH3 CH30 HCl 470.3 [M + H] +

 Example 344 *

   HCl 484.3 [M + H] +

 „, Och3 Kih C and JL f> NI i íl W N T'NT ° ACH3 ch3 ch3o

 Example 345 *

 ^ PCH3 r «fplXí" l v = <n ^ vnyaoach3 CHg I O ch3 HCl 484.3 [M + H] +

[Table 65.]

 Example 346 *

 - OCHg Kih (cnpl A yj N '^ YN'1f ^ o ^ CH3 ci ch3o HCl 503.2 [M + H] +

 Example 347 *

 okOCH3 (H ryiO, YA r = \ N iVo ^ chí F F CH30 HCl 506.2 [M + H] +

 Example 348

 pCH3 0 = <3 Kih f3c ch30 HCl 524.2 [M + H] +

 Examples 349 *

     538.2 [M + H] +

 o = <OCH3 NH ^ k, and A f3c ch30

 Example 350 *

 „DCH3 o = <J NH [„ Q-VvVo \ „. cf3 ch3o 538.3 [M + H] +

[Table 66.]

 Example 351 *

 oKOCH3 NH n '^ ynyaoa’ch3 ch3o HCl 488.3 [M + H] +

 Example 352 *

 ch3 ° Y °, NH i w iA Y Y / ro CH3 0 2HCl 445.3 [M + H] +

 Example 353 *

 o = <OCH3} „H o-w ch3o HCl 470.2 [M + H] +

 Example 354 *

   HCl 538.2 [M + H] +

 gch3 O ^ NH Hf> CH3 y- \ r .. ■ v. rfeii. jvj.jvj CH3 f3c

 Example 355 *

 okOCH3 NH / H ^ W V rNvCH3 f \ -u j. J, jr j S = / n ^ yn r ch3o HCl 470.3 [M + H] +

[Table 67.]

 Example 356 *

 H3CO Ch, 3 0 and ° N-N CH3 / = <f3c HCl 536.2 [M + H] +

 Example 357

 ch3 p ok NH f H A s y A í y-N Jl m 1 J \ = / n- \ Vo ch3o HCl 454.2 [M + H] +

 Example 358 *

 CHg p 0 = <Kih f H _ k Y rNVCH3 rvo i x y W naynt "oJ ch3o HCl 468.2 [M + H] +

 Example 359 *

 „PCHs 0 * (¿HH k y 0'NIn ^ yny ^ o ^ ch3 F CHsO HCl 488.2 [M + H] +

[Table 68.]

image25

 Example 361

 in, \ rJiyr ") ch3o HCl 429.2 [M + H] +

 Example 362

 ch3 OyO JlH [H 1 ch3o HgCOjS 2HCl 498.2 [M + H] +

 Example 363 *

 ch3 HEARD nh f ^ H rA Y v ch3o 2HCl 464.3 [M + H] +

[Table 69.]

 Example 364 *

 ch3 OYÓ rNH [_ H n i YS v ch3o 2HCl 464.3 [M + H] +

 Example 365

 CH3 <X ° NH) H 1 í í ci ch30 491.2 [M + H] +

 Example 366 *

 ch3 jm \ w - N'Y Y f} 2HCl 479.3 [M + H] +

 Example 367 *

 ch3 0 = <Ó kn [V H O ^ Vyny ^ 0 ^ cf3 ch3o 524.2 [M + H] +

[Table 70.]

 Example 368 *

 CH, Ó or <r. ryj * Y rVH3 ci ch3o HCl 521.2 [M + H] +

 Example 369 *

 ch3 ^ P OK NH / V Y A O ^ nA-nPoAf ch3o 488.3 [M + H] +

 Example 370 *

 ch3 or 0 = <kH {_ H / r \ Y rNYCH3 P'Vvny4 ^ F CH30 488.3 [M + H] +

image26

[Table 71.]

 Example 372 *

 QH3 ck ° HH ch3o 506.2 [M + H] +

 Example 373 *

 ch3 0 oH NÍH (^ H ^ ch) V = \ N ~ "C n> y-í or y- * ch3 Q- * ch3 2HCl 477.3 [M + H] +

 Example 374

 ch3 Heard, NH í H N i Y í¡ V ^ N * nt v ch3o 432.2 [M + H] +

 Example 375 *

 ch3 oyo NH [H N ^ N Y fY CH3 Jl JT kj 1 1 o ^^ Vnt'o ^ ch3 ch3o 435.9 [M + H] +

[Table 72.]

 Example 376 *

 r>. lj ■ w'ITg- ■■ ^ P o = <UH („H, rv-H Y r 1 ci ch3o HCl 520.8 [M + H] +

 Example 377

 ch3 0 = <NH (> and A ci ch30 HCl 506.8 [M + H] +

 Example 378 *

 CHs 0 NH u \ N-_ ^ 3 (<1 VN Vi I> wN ~ t | T b ch3w Cl HCl 550.8 [M + H] +

 Example 379

 _ch3 0 / N'N lj CHaXlY A ch3o 2HCl 415.9 [M + H] +

 Example 380 *

 ch3 or J? N-N u // ■ v p. ch3SA Y ii ^^ SrVoYHj ch3o 2HCl 429.9 [M + H] +

[Table 73.]

 Example 381 *

 0 ”CH3 hn'V v ch3'0 ^ NH ^ ° 0 * CH3 n-n Cl 534.9 [M + H] +

 Example 382 *

 ch3 0 or <ch3) ^ Vo V = \ ov pj ch3 2HCl 506.9 [M + H] +

 Example 383 *

 ch3 o »? ch3 fH HN '' \ P VH * r ° ck ch3 2HCl 508.9 [M + H] +

 Example 384 *

 ch3 P ch3 Q- * k O JMH HN - W uv lY / ^> CH3 ch3 2HCl 508.9 [M + H] +

 [Table 74.]

 Example 385 *

   2HCl 459.9 [M + H] +

 ch3 <S Ht ^ P'CHí S 4 yo NN N ‘-Qt H ° ch3 /

 Example 386 *

 ch3 1 JMH) \ „H CHsí I Y Í ^ T. n vo h3 gh3o 233.5 [M + 2H] 2+

 Example 387

 ch3 0 ck Jmh W vy ti ch3-A_ ^ n ^ Y r i \ J CH3 ° 497.9 [M + H] +

 Example 388

 oCHs> r-N u CH Vi Y rS ch3o 2HCl 416.0 [M + H] +

 Example 389 *

 0-CHS <u cWvW ch3o 2HCl 215.50 [M + 2H] 2+

[Table 75.]

 Example 390 *

     511.9 [M + H] +

 ch3 CH ° Kih {chY A / ^ vYnY ^ o'j> ch3 \ J CH3o

 Example 391

 ch3 OyO Íih CHjVn and A nA-Nyl0J ch3o 435.9 [M + H] +

 Example 392 *

 ch3 0) / 3 <r ~ N H chAA and A N ^ 'n'SAt'oJ'chs ch3o 2HCl 215.50 [M + 2H] 2+

 Example 393 *

 ch3 ch3 r ° óJ \ Af N-Cn CH3 CH3 2HCl 230.50 [M + 2H] 2+

 Example 394 *

 SH3 0-CH3 ° N HN-WU 3 S A Vo A ^ ryA1 0 n ~ Vn ch3 chA 2HCl 230.50 [M + 2H] 2+

[Table 76.]

 Example 395 *

     449.9 [M + H] +

 ch3 OyO, NH CH3 [_ H ^ Y A N '^ YNT gh3o

 Example 396

 ch3 CK ° ch3o 435.9 [M + H] +

 Example 397 *

 h3co Lk and JLch, ch3o 2HCl 429.3 [M + H] +

 Example 398 *

 £ H3 h3c y ~ o NY> h3C yq H3Oc> 479.9 [M + H] +

 Example 399

 qh3 OvO JMH [„H (i i1 ^ r i gh3o 421.9 [M + H] +

 [Table 77.]

 Example 400

   2HCl 490.9 [M + H] +

 H3C 3 0 0í = (u NH / \ ch3o

 Example 401

 och3 0 = <r », Jp? A0 H- ^ H ch30 489.9 [M + H] +

 Example 402

 H3C-0 hn-a <Mü. -to. y ° \ v ”° Y '2HCl 490.9 [M + H] +

 Example 403

 HsC-O ^ H0 0> -i ^ h 4 X ° T ^ cH ° CH3 O 473.9 [M + H] +

[Table 78.]

 Example

 Chemical formula Result MS Method MS Ionic Species

 Example 404 *

 HN or qH ^ .o H3CV ^ y% 0 496 ESI [M + H] +

[Table 79.]

 Example

 Salt chemical formula Result MS ESI Ionic Species

 Example 405

     491.9 [M + H] +

 Example

 Salt chemical formula Result MS ESI Ionic Species

 och3 G = <NH F v. v A AsA § 0

 Example 406

 'VA: or H> ° HQ v¡ ° / \ p 489.9 [M + H] +

 Example 407

 \ cV NH \ l V A = o 244.5 [M + 2H] 2+

 Example 408

 ■ ■ .... ■ ■ ■ ■ ......: 9 o = \ NH í ■ AvA - 0 244.5 [M + 2H] 2+

[Table 80.]

 Example 409

 EIGHT n_y 3 u ~ \ NH (r --- 7 H \ V nA „-VAL 1 i J J f s' '" A "' O ^ NT = O 488.9 [M + H] +

 Example 410

     256.5 [M + 2H] 2+

 och3 ° = £ \ NH / __ u Vi * o

 Example 411

 OCH, 0 .. \ NH l r--? H via v rX ¡J s y y o (/ * or 435.9 [M + H] +

 Example 412

 och3 0 = <NH <L V p jVs ^ "A- W'V ^ X" V- 488.9 [M + H] +

[Table 81.]

 Example 413

 \ 0 O ^ Á. NH / H 'lWrO ■ = o 476.9 [M + H] +

 Example 414

 \ 0/0 = \ NH okv «7 COOCHj = 0 530.9 [M + H] +

 Example 415

     476.9 [M + H] +

 \ 0 O-'Á NH / H = 0

 Example 416

 \ 0 o4 NH, _, H V V> ~ N Y f ^ N— / & I l 5 0 490.9 [M + H] +

[Table 82.]

 Example 417

 \ O NH i: \ Q ^ IrÓ V = 0 489.9 [M + H] +

 Example 418

 OCH, / 4 0 = K NH (/, _, H A, Y X "/ s r ir o ^ o 437.9 [M + H] +

 Example 419

 QCH3 Chíral o = (NH / H üW W í 0 479.9 [M + H] +

 Example 420

 Chiral Chiral o = and NH /, -, H V v \ 1 1 i oVr OH ° 453.9 [M + H] +

[Table 83.]

image27

 Example 422

 OCH, o = {NH / r-7 H OtWrO 4 l nh2 u 244.5 [M + 2H] 2+

 Example 422

 och3 0 == ^ NH k Y rS / = or 477.9 [M + H] +

 Example 424

 v 1. JMH and 0J = 0 HCl 478.0 [M + H] +

[Table 84.]

 Example 425

 och3 o = <NH <Y V A? 0 487.9 [M + H] +

 Example 426

 , PCH3 o = <NH / i ^ -7 H 1 Vi Y 1 0 475.9 [M + H] +

 Example 427

 och3 Q = <NH 1 Q 515.9 [M + H] +

 Example 428

 EIGHT 0 = <NH _ j- \ Y rY / y ^ Y-ny1'Y 489.9 [M + H] +

[Table 85.]

 Example 429

 QCH, .í. - »0 = \ NH / / m '. > i Y rNi {r ^ TV ° J V — J ¿0 238.5 [M + 2H] 2+

 Example 430

 EIGHT ■ / V o = <NH V-s and \ yesY> or 237.0 [M + 2H] 2+

 Example 431

 och3 o = (NH / H ViY rNi »2» 'A'Xsi ‘0 245.0 [M + 2H] 2+

image28

[Table 86.]

 Example 433

 1 ° Y ° JslH <YVS Y rY £ 0 HCl 478.1 [M + H] +

 Example 434

 och3 0 = (NH / H> sv Y rNi fVYyYo ^ ^^ CQOCHg ^ 3 0 529.9 [M + H] +

 Example 435

 och3 o = (NH $ Vs Y A ryVvyo ^ ^ Hs 0 502.2 [M + H] +

image29

[Table 87.]

 Example 437

 och3 0 = <NH / _ H V-S V ch3 O 475.1 [M + H] +

 Example 438

 och3 0 = <NH ti Y sS ch3 O 475.1 [M + H] +

 Example 439

 MN -— v ch¿A ^ S-0 H h Tí ^ __ / o lAo ° / "■ ch3 546.2 [M + H] +

 Example 440

     477.3 [M + H] +

Claims (10)

5 10 fifteen twenty 25 30 35 40 Four. Five fifty REIVIN DI CATIONS 1. A compound of formula [I]; image 1 wherein R1 * is a cycloalkyl or an alkyl, R22 is 1) an optionally substituted aryl, 2) an optionally substituted pyridyl, 3) an optionally substituted pyrazolopyridyl, 4) an optionally substituted indole, 5) an optionally substituted benzofuranyl, 6) an optionally substituted quinolyl, 7) an optionally substituted chromanyl, 8) an optionally substituted dihydrobenzofuranyl, 9) an optionally substituted indazolyl, 10) an optionally substituted pyrrolopyridinyl, 11) an optionally substituted benzisoxazolyl, 12) an optionally substituted indolinyl, 13 ) an optionally substituted quinazolinyl, 14) an optionally substituted dihydroquinazolinyl, 15) an optionally substituted furopiri dil, 16) an optionally substituted isoquinolyl, 17) an optionally substituted pyrrolopyrimidinyl, 18) an optionally substituted tetrahydroquinolyl, 19) an optionally substituted tetrahydroquinzolyl, 20) an optionally substituted tetrahydrocyclopentapyrazolyl, 21) an optionally substituted pyrrolyl, 22) an optionally substituted imidazolyl, 23) an optionally substituted pyrazolyl, 24) an optionally substituted thienyl, 25) an optionally substituted thiazolyl, 26) an optionally substituted triazolyl do, 27) an optionally substituted pyrimidinyl, 28) an optionally substituted pyrazyl, 29) an optionally substituted imidazopyridinyl, or 30) an optionally substituted pyrrolopyrazyl, R is a C1-C4 alkyl group, one of R4 and R5 is a group selected from 1) a carbamoyl optionally substituted with an alkyl that is optionally substituted with 1 or 2 phenyls, 2) an alkyl optionally substituted with an alkoxy optionally substituted with a halogen or a phenyl; a halogen; a hydroxyl; an amino optionally substituted with 1 or 2 alkyls; or cyano; Y 3) an alkoxycarbonyl, or a pharmaceutically acceptable salt thereof, the other, R3 and R6, are the same or different, a hydrogen atom, an optionally substituted carbamoyl, an optionally substituted alkyl or alkoxycarbonyl, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R3 and R6 are both hydrogen atoms, or a pharmaceutically acceptable salt thereof. 3. The compound according to any one of claims 1 to 2, wherein the substituents of 1) the optionally substituted aryl, 2) the optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 4) the optionally substituted indole, 5) the optionally substituted benzofuranyl, 6) the optionally substituted quinolyl, 7) the optionally substituted chromanyl substituted, 8) optionally substituted dihydrobenzofuranyl, 9) optionally substituted indazolyl, 10) optionally substituted pyrrolopyridinyl, 11) optionally substituted benzisoxazolyl, 12) optionally substituted indolinyl, 13) optionally substituted quinazolinyl, 14) optionally substituted dihydroquinazolinyl , 15) optionally substituted furopyridyl, 16) optionally substituted isoquinolyl, 17) optionally substituted pyrrolopyrimidinyl, 18) optionally substituted tetrahydroquinolyl, 19) optionally substituted tetrahydroindazolyl, 20) optionally substituted tetrahydrocyclopentapyrazolyl, 21) optionally substituted pyrrolyl optionally substituted, 22) optionally substituted imidazolyl, 23) optionally substituted pyrazolyl, 24) optionally substituted thienyl, 25) optionally substituted thiazolyl, 26) optionally substituted triazolyl, 27) optionally substituted pyrimidinyl, 28) optionally substituted pyrazyl substituted, 29) the optionally substituted imidazopyridinyl, or 30) the optionally substituted pyrrolopyrazyl in R22 are 1 to 3 groups selected from 1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from a alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, a 5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 60 aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen atom and an amino group optionally substituted with 1 or 2 alkyls, 2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen, 3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino, 4) a cycloalkyl, 5) a halogen, 6) a cyano, 7) an aliphatic heterocyclic group, 8) an aryl optionally substituted with 1 or 2 identical or different groups selected from an alkyl optionally substituted with an alkylsulfonylamino optionally substituted with a halogen and a halogen; a halogen; an alkoxycarbonyl; an ulfonylamino methane; a halomethanesulfonylamino; a methanesulfonylaminocarbonyl; a benzoylaminocarbonyl; a benzenesulfonylaminocarbonyl; a hydroxyoxazolyl; a hydroxyoxadiazolyl; a tetrazolyl; a hydroxyl and an alkoxy optionally substituted with an alkoxy, 9) a heteroaryl optionally substituted with 1 or 2 identical or different groups selected from an alkyl, an amino, a halogen and an alkoxy, 10) an aryloxy, and 11) an amino optionally substituted with 1 to 2 groups selected from an alkyl optionally substituted with an alkoxy and alkylsulfonyl, 12) an alkynyl optionally substituted with a hydroxyl, 13) an aliphatic heterocyclyloxy, 14) an arylcarbamoyl optionally substituted with an alkoxy, and 15) an alkanoyl, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 3, wherein the substituents of 1) the optionally substituted aryl, 2) the optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 4) the optionally substituted indole, 5) the optionally substituted benzofuranyl, 6) the optionally substituted quinolyl, 7) the optionally substituted chromanyl substituted, 8) optionally substituted dihydrobenzofuranyl, 9) optionally substituted indazolyl, 10) optionally substituted pyrrolopyridinyl, 11) optionally substituted benzisoxazolyl, 12) optionally substituted indolinyl, 13) optionally substituted quinazolinyl, 14) optionally substituted dihydroquinazolinyl , 15) optionally substituted furopyridyl, 16) optionally substituted isoquinolyl, 17) optionally substituted pyrrolopyrimidinyl, 18) optionally substituted tetrahydroquinolyl, 19) optionally substituted tetrahydroindazolyl, 20) optionally substituted tetrahydrocyclopentapyrazolyl, 21) optionally substituted pyrrolyl optionally substituted, 22) optionally substituted imidazolyl, 23) optionally substituted pyrazolyl, 24) optionally substituted thienyl, 25) optionally substituted thiazolyl, 26) optionally substituted triazolyl, 27) optionally substituted pyrimidinyl, 28) optionally substituted pyrazyl substituted, 29) the optionally substituted imidazopyridinyl, or, 30) the optionally substituted pyrrolopyrazyl as R22 is a group selected from 1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyls, 2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen, and 3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino, or a group selected from 1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyls, 2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen, and 5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 60 3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino, and 1 to 2 groups selected from 1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyls, 2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen, 3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino, 4) a cycloalkyl, 5) a halogen, 6) a cyano, 7) an aliphatic heterocyclic group, 8) an aryl optionally substituted with 1 or 2 identical or different groups selected from an alkyl optionally substituted with an alkylsulfonylamino optionally substituted with a halogen and a halogen; a halogen; an alkoxycarbonyl; a methanesulfonylamino; a halomethanesulfonylamino; a methanesulfonylaminocarbonyl; a benzoylaminocarbonyl; a benzenesulfonylaminocarbonyl; a hydroxyoxazolyl; a hydroxyoxadiazolyl; a tetrazolyl; a hydroxyl; and an alkoxy optionally substituted with an alkoxy, 9) a heteroaryl group optionally substituted with the same or different 1 or 2 groups selected from an alkyl group, an amino group and an alkoxy group, 10) an aryloxy, 11) an amino optionally substituted with 1 to 2 groups selected from an alkyl optionally substituted with an alkoxy and alkylsulfonyl, 12) an alkynyl optionally substituted with a hydroxyl, 13) an aliphatic heterocyclyloxy, 14) an arylcarbamoyl optionally substituted with an alkoxy, and 15) an alkanoyl, or a pharmaceutically acceptable salt thereof. 5. The compound according to any one of claims 1 to 4, wherein R22 is a group selected from 2) optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 7) optionally substituted chromanyl, 13) the optionally substituted quinazolinyl, 14) the optionally substituted dihydroquinazolinyl, 15) the optionally substituted furopyridyl, and 29) the optionally substituted imidazopyridinyl, or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of claims 1 to 5, wherein R22 is a group selected from 16) the optionally substituted isoquinolyl, 17) the optionally substituted pyrrolopyrimidinyl, 18) the optionally substituted tetrahydroquinolyl, 19) the optionally substituted tetrahydroindazolyl, 20) the optionally substituted tetrahydrocyclopentapyrazylyl, 21) the optionally substituted pyrrolyl, 22) the optionally substituted imidazolyl, 23 ) the optionally substituted pyrazolyl, 24) the optionally substituted thienyl, 25) the optionally substituted thiazolyl, 26) the optionally substituted triazolyl, 27) the optionally substituted pyrimidinyl, 28) the optionally substituted pyrazyl, and 30) the optionally substituted pyrrolopyrazyl, or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, wherein the substituents of 1) the optionally substituted aryl, 2) the optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 4) the optionally substituted indole, 5) the optionally substituted benzofuranyl, 6) the optionally substituted quinolyl, 7) the optionally substituted chromanyl substituted, 8) optionally substituted dihydrobenzofuranyl, 9) optionally substituted indazolyl, 10) optionally substituted pyrrolopyridinyl, 11) 5 10 fifteen twenty 25 30 35 40 Four. Five optionally substituted benzisoxazolyl, 12) optionally substituted indolinyl, 13) optionally substituted quinazolinyl, 14) optionally substituted dihydroquinazolinyl, 15) optionally substituted furopyridyl, 16) optionally substituted isoquinolyl, 17) optionally substituted pyrrolopyrimidinyl, 18) tetrahydroquinol optionally substituted, 19) optionally substituted tetrahydroindazolyl, 20) optionally substituted tetrahydrocyclopentapyrazyl, 21) optionally substituted pyrrolyl, 22) optionally substituted imidazolyl, 23) optionally substituted pyrazolyl, 24) optionally substituted thienyl, 25) thiazolyl optionally substituted, 26) optionally substituted triazolyl, 27) optionally substituted pyrimidinyl, 28) optionally substituted pyrazyl, 29) optionally substituted imidazopyridinyl, or, 30) optionally substituted pyrrolopyrazyl as R22 are a group selected from 1) an alkyl optionally substituted with 1 or 2 identical or different groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, a heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyls, 2) an alkenyl optionally substituted with 1 or 2 the same or different groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyls, an aryl, a hydroxyl and a halogen, and 3) an alkoxy optionally substituted with an alkoxy or an alkoxycarbonylamino, and a group selected from 1) an aryl optionally substituted with 1 or 2 identical or different groups selected from an alkyl optionally substituted with an alkylsulfonylamino optionally substituted with a halogen and a halogen; a halogen; an alkoxycarbonyl; a methanesulfonylamino; a halomethanesulfonylamino; a methanesulfonylaminocarbonyl; a benzoylaminocarbonyl; a benzenesulfonylaminocarbonyl; a hydroxyoxazolyl; a hydroxyoxadiazolyl; a tetrazolyl; a hydroxyl; and an alkoxy optionally substituted with an alkoxy; Y 2) a heteroaryl optionally substituted with 1 or 2 identical or different groups selected from an alkyl, an amino, a halogen and an alkoxy, or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 7, wherein R is a group selected from 2) an optionally substituted pyridyl, 21) an optionally substituted pyrrolyl, 22) an optionally substituted imidazolyl, 23) an optionally substituted pyrazolyl, 24) an optionally substituted thienyl, 25) an optionally substituted thiazolyl, 26) an optionally substituted triazolyl, 27 ) an optionally substituted pyrimidyl, and 28) an optionally substituted pyrazyl, or a pharmaceutically acceptable salt thereof. 9. A medicament for the treatment and / or prophylaxis of hypertension, heart failure, diabetic nephropathy and the like comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof. 10. A substance of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prophylaxis of hypertension, heart failure or diabetic nephropathy.